The story is told in a nonlinear manner. The following is a chronological summary of the plot:
Jack Jordan is a former convict who is using his new-found religious faith to recover from drug addiction and alcoholism. Paul Rivers is a mathematics professor with a dedicated wife, Mary, and has a fatal heart condition. Unless he receives a new heart from an organ donor, he will not live longer than a month. Mary wants him to donate his sperm so she can have his baby even if he dies. Cristina Peck is a recovering drug addict and now lives a normal suburban life with a supportive husband and two children. She is a loving mother and active swimmer who has left behind her days of drugs and alcohol. These three separate stories/characters become tied together one evening when Jack kills Cristina's husband and children in a hit-and-run accident. Cristina's husband's heart is donated to Paul, who begins his recovery.
Cristina is devastated by the loss and returns to drugs and alcohol. Paul is eager to begin normal life again, but he hesitantly agrees to his wife's idea of artificial insemination as a last-ditch effort to get pregnant. During consultations with a doctor before the procedure, Paul learns about an abortion that Mary had undergone after they had separated in the past. Angered, Paul ends the relationship. He becomes very inquisitive about whose heart he has. He learns from a private detective that the heart belonged to Cristina's husband and begins to follow the widowed Cristina around town.
Jack is stricken with guilt following the accident and starts using drugs again. Despite his wife's protests to keep quiet and conceal his guilt, Jack tells her that his "duty is to God" and turns himself in. While incarcerated, he clashes verbally with a pastor who had helped him after his last incarceration, claims that God had betrayed him, loses his will to live, and attempts suicide. He is released after Cristina declines to press charges against him, as she realizes that incarcerating Jack will not bring her family back. When Jack is released, he is unable to reincorporate himself into normal family life, and instead leaves home to live as a transient, working as a manual laborer.
Paul finds an opportunity to meet Cristina and eventually reveals how the two of them are connected. She is initially furious and forces him out, but soon reconsiders. Desperately needing each other, they continue their relationship. Though Paul has a new heart, his body is rejecting the transplant and his outlook is grim. As Cristina begins to dwell more on her changed life and the death of her family, she becomes obsessed with taking revenge against Jack. She goads Paul into agreeing to murder him.
Paul meets with the private detective who had found Cristina for him. The detective tells Paul that Jack is living in a motel and sells Paul a gun. Paul and Cristina check into the motel where Jack is staying. When Jack is walking alone, Paul grabs him and leads him out into a clearing at gunpoint intending to kill him. However, Paul is unable to kill Jack, who himself is confused, shaking and pleading during the event. Paul fires three shots into the ground and tells Jack to "just disappear," then returns to the motel and lies to Cristina about Jack's death. Later that night, while they are sleeping, Paul and Cristina are awakened by a noise outside their door. It's Jack, who, still consumed by guilt, orders Paul to actually kill him and end his misery. A struggle ensues, during which Cristina blind-sides Jack and starts beating him with a wooden lamp. Paul collapses, gets hold of the gun, and accidentally shoots himself.
Jack and Cristina rush Paul to the hospital. Still believing he deserves to be punished for his hit-and-run, Jack tells the police that he was the one who shot Paul, but is released when his story cannot be confirmed. Paul dies, and the conflict between Cristina and Jack remains unresolved (they meet in the waiting room after Paul's death; if they have a conversation, it is not shown). When Cristina offers to donate blood for Paul in the hospital, she learns that she is pregnant; the doctor urges Cristina to quit using drugs. After Paul's death, Cristina is seen tentatively preparing for the new child in one of her daughter's bedrooms, which she had previously been unable to enter after her daughter's death. Jack is shown returning to his family.
Sean Penn as Paul Rivers
Naomi Watts as Cristina Peck
Benicio del Toro as Jack Jordan
Charlotte Gainsbourg as Mary Rivers
Melissa Leo as Marianne Jordan
Danny Huston as Michael
John Rubinstein as Gynecologist
Clea DuVall as Claudia
Eddie Marsan as Reverend John
Marc Thomas Musso as Freddy
Paul Calderón as Brown
Denis O'Hare as Dr. Rothberg
Kevin Chapman as Alan
Lew Temple as County Sheriff
Carly Nahon as Cathy