The protagonist, Charles Schine (Clive Owen), is an advertising executive married to a schoolteacher in Chicago. The introductory scenes of the movie reveal that Charles' marriage is deteriorating due to the stresses of caring for a teenage daughter who is seriously ill with diabetes, while the parents both have busy careers.
While on a commuter train, Charles encounters an alluring woman named Lucinda (Jennifer Aniston) — he had forgotten his fare and was about to be thrown off the train when Lucinda offers to pay for it. The attraction is mutual, and the two begin meeting more frequently. Ultimately, the two are intent on consummating their affair in a shady hotel. Just as Charles and Lucinda are about to have sex, an armed man later named as Philippe LaRoche (Vincent Cassel) bursts into the hotel room, beats Charles and brutally rapes Lucinda. Charles and Lucinda agree not to report the crime, as they do not want their spouses to learn of the affair. Shortly after the incident, Charles is blackmailed by LaRoche, who threatens to kill Charles' family if he doesn't pay $20,000, which Charles soon pays. But a month later, the attacker calls again, demanding $100,000 — and he's calling from Charles' house. Charles rushes home to find LaRoche visiting with his wife Deanna (Melissa George) and daughter Amy (Addison Timlin), posing as a business associate and much to his disgust he appears to be exceptionally pleasant to his family.
Charles has a friend, Winston Boyko (RZA), who works in the mailroom at work and has done jail time. Winston admits to killing a man while in prison. Charles tells Winston about LaRoche and asks for advice. Winston offers to scare LaRoche away in return for 10% ($10,000) of LaRoche's demand. As they prepare to approach LaRoche in Winston's car, Winston shows Charles the shank (make-shift knife) he used in prison. He gives it to Charles for good luck. But LaRoche is a step ahead, and shoots Winston dead through the window in his car. The murder is almost discovered by a couple of corrupt cops flirting with a prostitute named Candy (Georgina Chapman) — and Charles barely escapes being implicated in the murder. Charles has to clean up the crime scene, so that he won't be suspected of the murder himself. He attempts to do this by driving the car into Lake Michigan, but the car gets stuck on the shore and Charles flees at the sound of approaching police sirens.
The next day, Charles is questioned by a police detective named Franklin Church (Giancarlo Esposito), who is also Winston's uncle, about his coworker. Later, Charles receives a call from LaRoche — he's got Lucinda at gunpoint, and will kill her if Charles doesn't bring the $100,000 immediately. Charles does by taking money from an account meant to provide for the daughter's medical treatment. The payoff complete, he and Lucinda say a tortured goodbye.
That night, Charles confesses to his wife that he has spent the money they had been saving for seven years. Although he is not shown confessing the affair, it is suggested that he does when he says "I'll tell you everything. And it's not just about the money."
Before another meeting with Detective Church, where Charles plans to tell the whole story, he decides he first has to let Lucinda know. He stops by her office, where he discovers she's not who she said she was. Lucinda Harris was a real financial adviser's name, in the person of a black woman, pinpointed to by the blonde receptionist when Schine asks for Aniston's presence at the counter. Here, Schine (Owen) becomes suspicious.
Charles immediately goes to the condo unit (room 4101) to check if "Lucinda" was there, thinking she might have been kidnapped again by LaRoche. Upon arriving, he sees a lady "condo seller" (lady in wine red overcoat) engaged in a pitch to sell the unit. The lady gives Charles a brochure, where he sees the cover (a girl standing in a tire swing) similar to the wallet picture "Lucinda" shows off at their train ride as her acclaimed daughter. Schine gets his second "clue".
Charles plans to track down "Lucinda's" where-to. He goes to the same train station they met, and waits, in the possibility of seeing her, for Lucinda outside a train. Indeed, Lucinda steps out and heads to an unknown direction. Charles continues the until he witnesses an unexpected scene in which he learns that Lucinda was in on the scam from the beginning; it was a setup. He watches "Lucinda" meeting up with Laroche, by a shiny black limousine, and kisses him amorously; Lucinda and LaRoche are actually lovers. Charles is dumbfounded.
Charles tracks Lucinda in the restaurant where they used to have dinner. Lucinda is seen with another scam 'victim', a married guy. Lucinda calls LaRoche and his hencemen Dexter (Xzibit) to let them know they're heading for the same motel.
Charles tracks Lucinda and the guy back to the hotel, where she, LaRoche and Dexter are setting up yet another mark.
Lucinda and the guy go inside the room and begin foreplay; Charles waits for LaRoche to approach that room, and then knocks LaRoche unconscious before he enters. Charles breaks in with an unconscious LaRoche in his hands. Lucinda is shocked by Charles' sudden arrival and denies their acquaintance when asked by her intended victim. Charles shoots LaRoche and demands his money back. Dexter enters the room and a gunfight ensues. It appears that everyone but Charles dies, including Lucinda, LaRoche, Sam Griffin (David Morrissey) and Dexter. Charles wipes his prints from the guns and slips away. On the way out —as the police are emptying the hotel safe— Charles sees his old briefcase. He reclaims it and finds that it still has his $100,000 in it.
The next day, Charles gets busted for embezzling at work (he scammed $10,000 to pay his coworker, Winston, to help him), and is sentenced to six months of community service, teaching at a prison. It turns out that LaRoche survived the gunfight, and is an inmate at the prison. After his class assignment, Charles picks a blue booklet, among his class's other booklets, with a black pen scribbling "Sidetracked." He reads on and finds out that it was about him. The conclusion of the story in the booklet tells Charles to enter the laundry room. Upon his arrival there, LaRoche taunts him, only to find that Charles tracked him here on purpose, to finish the job. Charles stabs LaRoche to death with the shank given to him by Winston.
Upon departure, Charles meets Detective Church. He claims he was attacked and acted in self defense. Church is suspicious, but has no evidence upon which to do anything other than let Charles go free, after which he is reunited with his wife and daughter.
The track that plays during the trailer is called Offshore, by Chicane. The track at the beginning of the trailer is actually called "Breathe Me" by Sia