Into the new millennium, more new characters were introduced, including Lindsay's (Catherine Hickland) sister Melanie (Darlene Vogel) and her husband Colin (Ty Treadway). Colin was killed, but his twin brother was brought on the canvas, only to lose his mind and become a killer. Phelps' tenure saw the departure of a number of long-running actors, such as Laura Koffman (Cassie), Clint Ritchie (Clint), and Strasser (again).
When Phelps and McTavish left in early 2001, they were replaced by executive producer Gary Tomlin and writers Lorraine Broderick and Christopher Whitesell. Many of the actors hired under Phelps' tenure were let go. Fan favorite Gabrielle returned after a ten-year absence and romanced Max, then Bo. Storylines became more campy; and the show had a much-acclaimed week in May 2002 where the episodes were broadcast live. This experimentation was mixed with truly dark tales such as Todd selling Blair's baby, telling her the child was dead and then passing him off as an adopted baby when he realized he was the natural father. Another story involved Viki returning to her former split personality Niki Smith to block out the painful memory of being raped by Mitch Laurence (Roscoe Born). She had one child with Clint (Natalie) and the other child (Jessica) was fathered by Mitch. Another storyline was Antonio (Kamar de los Reyes) having a one-night stand with a woman who turned out to be his fiance Keri's (Sherri Saum) mother, Liz (Barbara Niven). She then implanted her embryo into Keri, meaning that Keri was unknowingly giving birth to her fiance's child. To the chagrin of many viewers, much airtime was devoted to Lindsay's daughter, Jen (Jessica Morris).
In early 2003 Malone and Josh Griffith were rehired as head writers with Frank Valentini taking over as executive producer. A new major storyline involved Mitch kidnapping sisters, Natalie and Jessica, to figure out which one's heart was a match for their grandfather. Victor had been faking his death. He was too ill to have major confrontations with his children and died a few weeks into the story. Dorian then showed up as Mitch's new bride, and she became immeshed in a storyline involving a jewel hunt as well as a "curse" which blinded Mitch. Mitch was later killed by Jessica. Another story involved the return of Cord and Tina's daughter, Sarah Roberts, as rock singer Flash (Shanelle Workman). Flash dated, and even kissed, Joey Buchanan (Bruce Michael Hall), her cousin. Joey, who was a minister at the time, then married Jen Rappaport, but the marriage did not last due to her affair with former husband Rex Balsom. Joey was then sent back to London to live with Clint.
Roger Howarth had come and gone several times but quit for good in early 2003. Mitch had him kidnapped. When the character returned several months later, he was posing as Mitch's brother Walker and was played by Trevor St. John. Apparently Todd had been so badly beaten that he had to get extensive plastic surgery. In spite of much fear that viewers would never accept any other actor as Todd, the talented St. John became popular and Todd, for the first time in a decade, had love scenes as well as a semi-functional relationship with Blair.
In April 2003, Dorian Lord returned with plans to strike it rich. She married Mitch Laurence claiming she "loved him". It was later found out that she married him to pay him back for the harm he did to the Cramer and Buchanan families. Viki developed heart trouble and was saved by a heart transplant from her comatose husband, Ben. One of the most appreciated storylines of the second Malone/Griffith era was Marcie Walsh (Kathy Brier)'s struggle with her self-esteem and her love story with Al Holden (Nathaniel Marston). Inexplicably, Marston was fired, while Al was killed off despite the couple's immense popularity. But a write-in campaign led by Marcal fans convinced ABC to rehire Marston, in spite of his character having died on screen. Al's spirit took over Michael McBain's body, causing the ghost to lose all memories as Al, and court Marcie as Michael McBain. Brooding actor Michael Easton (who had a following as Stephen Clay/Caleb Morley, a singing vampire, on Port Charles) was hired as Michael's cop brother John McBain. John had affair with Llanview's Top Lawyer Evangeline Wiliamson (Renee Elise Goldsberry) that quickly turned into a relationship. Al's mother, Gabrielle, was murdered by the Music Box Killer, and Al's father, Max, left town, thus removing the Holden family from the canvas. Next came the saga of the Santi mobster family, whom Antonio learned he was related. To the detriment of ratings (which fell to an all-time low in the summer of 2004), much of the action centered around new characters: Antonio's brother Tico (who married Jessica Buchanan), stepsister Sonia, and mother Angelina.
Writers Malone and Griffith chose to leave, and were replaced by Dena Higley in December 2004. On the day he was to remarry Blair, Todd was kidnapped by the crazed Margaret Cochran, who in an homage to Misery, tied him up for weeks in a secluded cabin while he recovered from his injuries. She then forced him to have sex (rape) to impregnate herself, in a throwback to his past history of rape. Margaret then conspired to get rid of Todd's wife, Blair by locking her in the trunk of her car. Margaret became pregnant and stabbed Todd because he tried to strangle her. To keep her away from his family Todd took Margaret to a lake and she never came back to shore. A few weeks later, her body and the unborn child washed up on shore. Todd was arrested for the crime and was tried for first degree murder and sent to death row. Todd was trying to prove his innocence, with the help of Evangeline (his lawyer), but did he or someone else kill Margaret?
A storyline played out in 2005 in which Nora's (Hillary B. Smith) new husband Daniel Colson (Mark Dobies), was revealed to be Paul Cramer's murderer. He first framed his son's girlfriend Jennifer Rappaport (Jessica Morris) for the crime, and then strangled her when she learned the truth. But the revelation that his killing spree was all to cover up his homosexuality proved controversial in the media.
During this time Natalie's husband Cristian Vega was in Statesville Prison. Attorney Evangeline Williamson took over his case and won which lead to the release of Cristian Vega. After Cristian's release Evangeline and Cristian grew closer and fell in love.
Nora's health took a downturn after she suffered a massive seizure during an argument with Bo about Paige. She remained in coma for several months but eventually made a full recovery.
Jessica, meanwhile, developed a split personality into bad girl "Tess" who goaded Viki into having a heart attack. Jess/Tess become pregnant either by Jessica's boyfriend Antonio or Tess' boyfriend Nash (who has a past of his own). Concerned that the baby was actually Antonio's, Tess destroyed the sample that would identify the actual father. Viki meanwhile emerged into Niki Smith and kidnapped Jessica forcing her to become Tess to finally discover what made Tess emerge that would destroy Viki forever. Tess refused to tell Niki her secret because if anyone knew, Jessica would integrate into the dominant personality. Determined to know what happened to their daughter, Viki and Clint returned to the bar where Niki had taken Jessica when she was child. The evidence pointed to a house a couple of blocks away from the bar. There they discovered VHS tapes buried underneath the house with Tess' name and other girls names on the tapes. Viki and Clint decided to give the evidence to Bo, but before Tess' tape could be released to the police, Viki and Clint begged Bo to see what had happened to their daughter. Jessica gave birth to a little girl named Brennan (or Bree for short) and the paternity was later reveal to be of Nash. Tess and Jess were later integrated, and Jessica married Antonio Vega.
May 2006 was a month of tragedies and happier times for Llanview. Duke Buchanan, son of Kevin Buchanan, was injured after a tornado wreaked havoc on the town during Michael McBain and Marcie Walsh's wedding. Kevin was heartbroken as he was forced to choose who would get a life saving surgery and chose Kelly over Duke. Kelly survived but Duke died. Kelly became pregnant with Duke's baby and later gave birth to premature baby, Zane. Kelly, Kevin, and the baby left Llanview to start life anew in London.
It turned out that Spencer Truman, revealed to be David Vickers' half brother, framed Todd Manning by faking Margaret's death, wiping her memory, and gave Margaret's baby away. David Vickers, Natalie Buchanan, and John McBain later found a very much alive Margaret in Thailand. She had no memory of what happened to her or her baby. On Todd's execution day, John stormed into the execution chamber with Margaret in tow. By then, Todd had already been given the injections and Blair was devastated. Blair was shocked to find that Margaret was alive and Todd was telling the truth all along. She begged Spencer to save Todd and he did.
Meanwhile, the police talked to Margaret about what happened. She did not remember anything of what happened but later regained her memory during transport to jail. Unfortunately, the van she was in got into an accident and she was killed.
Later, Blair realized that Spencer was indeed behind the framing of Todd. She helped the Llanview police by getting proof that Spencer may have killed John's father not David as once thought. He was arrested and put on trial.
In August 2006, Dorian's daughter Adriana was kidnapped by Bruce Bartlett, and held for ransom. Bruce was killed and Adriana was rescued by Rex and Dorian, but the damage was done. Adriana was angry at her mother's involvement. Dorian had hired Bruce to stalk Adriana because she despised Adriana's boyfriend, Rex, and did everything to break them up. Adriana moved out but later reconciled with her mother on Christmas, at the urgence of Carlotta.
Hugh Hughes learned that Paige and Spencer were his biological parents. Just after Hugh found out about that, there was a major car accident that he and John McBain were in. Michael McBain went with Bo to identify the body and it turned out to be John. Everybody thought that John had died. However, later, everyone soon learned that John was the one in a hospital burn unit, and Hugh was the casualty. After being released to a sterile environment, John faield to take his medication properly, forcing Natalie to put it in his food. John discovered Natalie's doings, and they broke-up.
Cristian's return from the dead didn't thrill the art world, so Cris became a boxer. New arrival Vincent Jones became Cris' manger, but was working to make it look as though Cris botched a fight. Cris lost his boxing career, and Vincent was cleared of all charges. However, Layla was not willing to forgive Vincent, until after an encounter with death. A racist arsonist began targeting Llanview, causing the death of Ted Osbourne and the catatonia state of Evangeline Williamson. Nearly killing Vincent, Layla, Adriana, and Rex, all were shocked to learn that ex-baseball player Tate Harmon was the arsonist. Tate was apprehended and sent to prison.
Starr Manning found new love with a boy named Cole. After a roid rage on Cole's part, Cole was arrested, and the Manning's were baffled to discover that Cole was the son of Marty Saybrooke and Patrick Thornhart. With their parent's forbidding them to see one another, Starr and Cole eventually continued their relationship in secret. Overcoming several roadblocks, Cole and Starr got their happy ending during Prom Night. Due to the threat of Lee Ramsey, Todd set plans to move his family to Hawaii, forcing Starr to have one last spencial night with Cole. Cole and Starr made love for the first time, but were interrupted by Todd. Surviving Todd's multiple beatings, Cole was again forbidden from seeing Starr. But Starr soon learned that she was pregnant, and telling Cole, running away. Todd caught up with them, with Blair learning the truth. Wanting Marcie and Michael to adopt her baby, Starr began fighting with Cole, who wants to keep the baby as a legacy of his deceased parent's. Cole came clean with Todd about the pregnancy, and the two are now working together to prevent Starr from giving the baby away.
Spencer was deemed unfit to stand trial, and was to be sent to Wingdale. Todd abducted Spencer and tortured him for information on the wherabouts of his missing son with Margaret. In a freak accident, Todd, Spencer, and Blair ended up on the roof of the warehouse, where Blair and Spencer fell. Both survived, and Blair revealed to Todd that she was pregnant with his child. Blair soon miscarried, and was diagnosed with a heart diease, but survived. Spencer killed his attorney, Marc Casey, and nearly raped Blair until an unknown assailant stabbed his repeatedly from behind. Michael, Rex, David, and Marty were each arrested for the murder, but Lindsay turned out to be the true culprit. Lindsay's motive was to silence Spencer in order to keep the truth from Marcie that Tommy (her adoptive son with Michael) was really Todd's son. Rex (who knew the truth about Tommy) gave Todd a phony death certificate, but Todd soon got a lead on his son, which took him to Chicago. Todd was stabbed and went missing, later turning up in the apartment of Hunter Atwood, the boyfriend of Sarah Roberts. Todd was soon free, and Hunter was accidentely stabbed by Cristian Vega. Miles Laurence gave Todd proof that Tommy was his son, and Todd interrupted Lindsay's murder trial to reveal the truth. Todd soon won custody, but Marcie kidnapped Tommy and went on the run. Marcie was eventually apprehended and Tommy was given back to Todd, renamed Sam. John blackmailed Todd into dropping the charges against Marcie and posting her bail.
Miles Laurence, brother to Mitch, arrived in town as Spencer's heir. Miles spent his entire life in an institution due to the fact that his family wanted nothing to do with him because of the tumors on his face. Spencer replaces Miles' face, thereby making Miles eternally indebted to Spencer. Experiencing his firsts, Miles fell in love with Marty. Suffering from panic attacks, Marty remembered killing Spencer, and admitted so to her phychiatrist. Miles got his hand on the tape used to record Marty's session, and used this to blackmail Marty into marrying him. Marty had no choice but to give in to Miles' blackmail, and she married him. Learning that Miles was holding a missing Todd captive and blackmailing Cole, Marty turned Miles in. Miles was later released on bail, and was befriended by Natalie. Miles was devastated to learn that Marty died in an explosion as the result of a showdown with Irish terrorists.
Lindsay faked a nervous breakdown, and was institutionalized. Nora suspected that Lindsay faked her condition, but never gained proof. Lindsay was released into the custody of Bo, and the two began to fall in love once more. Lindsay received a letter from R.J. that soon got mixed up in Nora's paperwork. Lindsay got her hands on the letter, burning it, but not realizing that Nora's assistant had made copies of all of the papers. Nora read the letter, ending Bo and Lindsay's marriage before it began. Lindsay was arrested, and plead guilty to murder during her trial.
Clint fell in love with Dorian, but his returning feelings for Viki weren't as strong, and he chose Dorian. After the death of Asa Buchanan, Dorian learned that Langston Wilde was an orphan living on her own since her parents' death over a year earlier. Dorian became Langston's foster mother, which caused Dorian to miss out on the reading of Asa's will. However, Dorian made is to Texas with the newly married David Vickers and Alex Olanov. Dorian caught Clint and Nora in a liplock, and slept with David. Clint walked in on them, and broke things off with Dorian.
Breaking up with Evangeline for kissing Todd, Cristian began to suspect that Jessica and Nash were fooling around behind Antonio's back. Jess convinced Cris that this wasn't the case. Antonio asked Jess to adopt Jamie and become her mother, but Jess ran out of the court room during the adoption hearing. She ended up in the arms of Nash, and they made love for the first time. However, Jessica collapsed in Antonio's arms as she was about to tell the truth. But before the truth could come out, Jess was diagnosed with Hepatitis C and liver cancer as a result of Tess sharing heroin needles. The truth came out, and Antonio left Jess and the country, only to become a match for a liver transplant. The transplant was successful, but after their divorce hearring, Jess was back in the hospital, where her body rejected Antonio's liver. David was also found as a match, and just before surgery, Nash married Jessica. The transplant was successful, but David wanted $10,000,000 before he agreed to the transplant. Viki learned the truth, and in an attempt to regain their friendship, David gave to money back to Clint and Viki forgave David.
After being cleared of Spencer's murder and annuling her marriage to Miles, Marty began a relationship with John. But, during the search for Marcie, Marty was abducted by an Irish terrorist, and was reunited with Cole in Ireland. John and Ramsey arrived on the scene, forcing terrorist Simon to take Marty and Cole in a van. Ramsey shot the vans tires, causing the van to go over a cliff. Cole was thrown from the vehicle, and survived. Marty did not. However, Ramsey was nursing a mystery woman back to health. This woman turned out to be Marty. After Ramsey's murder, Todd discovered an amnisiac Marty, and began taking care of her, failing to share their past history.
Tina Lord, princess of Mendorra, returned to Llanview looking for the crown jewels of Mendorra, which had been stolen by Ramsey. After Ramsey was murdered, Tina took the jewels, only to be held at gun point by American ambassador to Mendorra Jonas Chamberlain. As Cristian and Sarah hid Tina, Jonas came upon Talia, who he forced to trick Sarah into a trap. Jonas took Talia and Sarah to Mendorra, where Carlo Hesser revealed himself as Talia's father. Antonio was beyond not pleased to learn of this truth, while Sarah was reunited with Tina and Cristian. Tina's prince turned out to be none other than Cain Rogan.