Mark Greene, an only child, was raised by his mother, Ruth, and father, David. David Greene served in the United States Navy, and thus the family moved frequently. Mark had a very strained relationship with his father, and was decidedly closer to his mother. He'd often act out in an attempt to upset his father, and aimed his goals in the opposite of what his father wanted. The most memorable time of his childhood was when his family was in Hawaii, a time he would later recreate during the last few weeks of his life.
Mark entered medical school, married Jennifer (Jenn), with whom he had a daughter, Rachel. He completed his internship and residency in the Emergency Department of County General Hospital in Chicago, Illinois.
In the pilot episode, which takes place on St. Patrick's Day 1994, Dr. Greene is chief resident in the ER of County General. Dr. Greene is awakened in the first scene to help sober up his long-time friend, Doug Ross, a pediatrician also on duty in the ER. Within the same episode, Jenn gets Mark to visit a private practice near the hospital to explore the possibility of leaving his job at the ER, to give him more family-friendly hours. Mark decides the "clean" medicine isn't his cup of tea. Mark removes a hangnail from an older woman, who wanted him to remove it despite the fact she'd be charged $180. Later that same day, Mark urges the ER staff to continue working when Nurse Hathaway is brought in after a suicide attempt.
During the first season, Dr. Greene's marriage becomes increasingly shaky. When offered an attending physician's position by David Morgenstern, Mark readily accepts, much to Jenn's chagrin. As a newly-admitted member of the bar, Jenn has been clerking in Milwaukee for a judge and becomes increasingly tired of commuting and living separately to accommodate Mark's job. She begins an affair with a coworker, and the marriage soon ends, with Rachel and Jenn leaving Chicago first for Milwaukee, and later for St. Louis, Missouri.
In "Love's Labor Lost", Mark made miscalculations in treating a pregnant woman that led to her death in childbirth, and the after-effects of this case lingered long into Season 2.
Mark's career becomes more difficult as he begins needing to make decisions that periodically alienate his friends, such as selecting Dr. Kerry Weaver over another applicant, which angered Susan Lewis first because the other applicant was a good friend of hers, and later because she bristled under Kerry's demanding, sometimes harsh leadership style. His friendship with Dr. Ross becomes strained as his administrative tasks often put him at odds with Doug's wild ways and he was disgusted by Doug's personal problems to the point where he briefly overruled and belittled Doug's abilities as a physician, then reconciled with his friend. His love life took a more drastic downward spin when his feelings for Dr. Lewis became so noticed that he's driven to ask her out, only to have her leave for Phoenix, Arizona. He suffers emotionally again after he is attacked in the ER men's room in the episode "Random Acts", initially believed to be a retaliatory act to avenge the death of a patient who may have been "mistreated" by Dr. Greene because of the patient's race. Later on, though, it was strongly implied that his assailant was a psycho who was randomly attacking doctors. Mark bought a gun and later used it to scare away a crowd of punks on a train, but decided to toss the gun in the river soon afterwards. He would struggle through a large part of Season 4, but came to terms with it in Season 5 when he helped Nigerian-born janitor Mobalage reveal his memories of torture by talking about the attack with him, allowing him to get political asylum and avoid deportation.
With the passing of Doug's father comes the re-entrance of Mark's parents. He and Doug travel to California to settle Doug's father's affairs and take a side trip to visit Mark's parents, who live in another part of California. His relationship with his father David is strained, and his mother soon suffers from a string of medical conditions associated with aging. Mark also finds out that his mother viewed his birth as a mistake, since she didn't know his father well and had to get married quickly. Mark's distrust of the Navy puts him at odds with David when he and Mark fight over whether Ruth should be treated in a base hospital or a civilian hospital. Ruth eventually dies and Mark goes to her funeral, leaving him on edge when he clashes with Kerry Weaver over Robert Romano's successful drive for Chief of Staff.
Mark's personal life after his marriage is tumultuous. He takes after Doug, having several flings and an affair with Nurse Chuny Marquez, and even setting up three dates in one day. He has a brief relationship with a needy desk clerk, Cynthia Hooper (played by Mariska Hargitay in season 4). Hooper leaves him after she finds out Mark doesn't really love her. Mark eventually meets a British surgeon, Elizabeth Corday. Corday is in Chicago on an exchange program, under the guidance of Dr. Romano. Romano's advances on Corday fail, as does her relationship with Peter Benton. Eventually, Mark and Elizabeth begin dating. By this time, David Greene's lung cancer has advanced to a stage where he can no longer care for himself, and he reluctantly moves to Chicago and stays with Mark. After an emotional bonding that healed their difficult relationship from Mark's youth, David succumbs to lung cancer.
Mark and Elizabeth begin a more serious relationship and move in together. Mark later buys a house, and Elizabeth and he are married. Together they have one daughter, Ella. Their happiness is threatened, though, when the abusive father of a patient goes on a killing rampage after losing his son to social workers. In a bid to get his son back, he kills and injures a number of people and even threatens to kill Elizabeth and Ella. After being shot by police, he is brought to the ER. During his treatment, he is being transferred by Mark to the operating room when he goes into arrest. Alone in the elevator, Mark decides to withhold treatment and allows him to die. He later falsifies records to show that he did attempt to save him. Elizabeth suspects what Mark did but lets the matter drop without any further discussion. Later, Rachel appears in Chicago unannounced, citing arguments with her mother, and moves in with Mark and a very reluctant Elizabeth. She is found to be sneaking out of the house at night and using drugs, which clouds her relationship with her stepmother Elizabeth.
At this point, Rachel has run away from St. Louis and is staying with Mark and Elizabeth. Though she vehemently denies it, her recreational drug use becomes apparent when baby Ella gets hold of some ecstasy in her backpack and nearly dies from ingesting it in the episode "Damage is Done". When Mark refuses to throw Rachel out of the house, Elizabeth says she won't return home with Ella as long as Rachel is there and, with Ella, Elizabeth leaves Mark and moves into a hotel. Unwilling to tell Elizabeth about his condition, Mark stays with Susan Lewis during the course of his chemotherapy and radiation treatments.
Eventually, however, he resigns himself to certain truths and decides to halt the treatments. On his last day in the ER, he meets with the same older woman that viewers saw on the first episode of ER. She again has a hangnail, and complains about how painful it is. Mark tells her that he has an inoperable tumor, tells another doctor to treat her, and tells the patient not to return to the ER again. He leaves the ER, stops his chemotherapy treatments, tells John Carter that he will now "set the tone", and takes Rachel on a last-minute trip to Hawaii to relive happier times.
After several moves around the island, he suffers from increased symptoms, prompting Rachel to call Elizabeth, who comes to Hawaii with Ella. One night, Rachel comes to Mark's room while he sleeps. Mark awakens and smiles at Rachel, telling her with slurred speech that he was just dreaming of her and how she used to love balloons. He tells her that he was trying to think of a piece of advice that every father should tell his daughter, and tells her to be generous with her time, her love, and her life. Rachel tells Mark that she remembers a lullaby that Mark used to sing her when she was a baby and slips a pair of headphones on his head and plays Israel Kamakawiwo`ole's rendition of "Somewhere Over The Rainbow" for him as he smiles and falls back asleep. While the song plays, he is seen walking through an empty ER (his entrance to heaven). The next morning, Elizabeth discovers that he has passed away.
Mark's body is returned to Chicago, where he is buried. Many of his friends and colleagues come to the funeral: John Carter, Peter Benton, Kerry Weaver, Abby Lockhart, Luka Kovač, Susan Lewis, Jing-Mei Chen, Robert Romano, Jerry Markovic, Frank Martin, Donald Anspaugh, William "Wild Willy" Swift (played by Michael Ironside in 1994), Haleh Adams, Michael Gallant, Cleo Finch, Jenn, Rachel, Ella, and Elizabeth. After the funeral, Rachel asks Elizabeth if she can visit to see Ella; Elizabeth responds "Of course, she's your sister". Rachel goes back to living with her mother in St. Louis, but later returns to Chicago when the time comes to select a college.
Dr. Mark Greene was written out of the series because actor Anthony Edwards had decided that he wanted to move on to other opportunities. Dr. Greene did appear in photos included in the slideshow shown at Dr. Carter's farewell party in the Season 11 episode "The Show Must Go On". Greene was also heard in a voice-over telling Carter that he needed to "set the tone" in the ER (which, incidentally, was what Dr. Morgenstern told Dr. Greene in the pilot episode). In the Season 12 episode "Body and Soul", he is mentioned during a flashback to 2002, when Dr. Pratt tells his patient, Nate Lennox (James Woods), that the reason the ER has few staff working is because they are at Greene's funeral. In Season 14's "Blackout", Nurse Chuny Marquez says that she can't believe the ER is going to be led by Pratt and Morris, and says how she remembers when Mark Greene and Doug Ross used to run the place. Nurse Sam Taggart then says, "Who?", since she started working in the ER long after they had left.
In 2008, E.R. producers announced that Edwards would reprise his role for the series' final season, with Dr. Greene appearing in flashbacks.