The narrative of My Sister’s Keeper alternates between first-person accounts by the novel’s different characters. The bulk of the story takes place in the present, in a one-and-a-half week stretch of time. Sara Fitzgerald, a former attorney and current stay-at-home mom, narrates the remainder of the story from different points in the past but moving gradually toward the present. One final chapter, the epilogue, occurs in the future. In 1990, doctors diagnose Sara’s two-year-old daughter, Kate, with a rare and aggressive form of leukemia. The news that their child might die shocks Sara and her firefighter husband, Brian, but Sara immediately resolves to begin Kate on treatment. Kate starts chemotherapy, and her oncologist, Dr. Chance, suggests she might eventually need a bone marrow transplant, preferably from a related donor. The Fitzgeralds test their four-year-old son, Jesse, but he is not a match. Dr. Chance mentions that another unborn sibling could be a match, and Sara suggests to Brian that they have another child.
Sara’s passages, told at different points over the next fourteen years, focus largely on Kate’s struggles. She describes how scientists help them conceive another daughter, Anna, who is a perfect genetic match for Kate. Over the course of the next few years, Anna undergoes several procedures, including frequent blood withdrawals and a painful bone marrow extraction, to help keep Kate alive. Sara describes in great detail the pain and suffering Kate endures. Chemotherapy and radiation make her violently ill, and an emergency trip to the hospital heralds each new relapse. Sara and Brian’s marriage suffers as a result, to the point where they begin to feel like strangers. In different ways, both Jesse and Anna act out at Sara because of her single-minded focus on Kate.
The present action of the story begins on a Monday. Thirteen-year-old Anna goes to see a lawyer named Campbell Alexander and asks him to represent her. Anna tells Campbell that she wants to sue her parents for medical emancipation. Kate, her sister, is in the end stages of kidney failure, and Anna wants to file the lawsuit so she will not have to donate a kidney to Kate. Campbell, who has a service dog but gives a sarcastic explanation whenever someone asks why, agrees to represent Anna for free. When she is served with the papers for the lawsuit, Sara becomes furious with Anna as she cannot understand Anna’s decision. Brian, however, understands Anna’s point of view to a degree and recognizes that she would not have brought a lawsuit unless she were genuinely unhappy. Judge Desalvo, the judge for Anna’s case, decides to appoint a woman named Julia Romano as Anna’s guardian ad litem, a person whose job is to objectively decide what is in Anna’s best interests. When Julia goes to see Campbell, it becomes clear they have a romantic past and have not seen each other in many years. Throughout all of these events, Jesse has been setting different abandoned buildings on fire. Jesse acts like a delinquent in other ways as well, such as drinking alcohol excessively, but much of this behavior stems from anger over his inability to save Kate and his feelings of being ignored by his parents.
Kate becomes seriously ill and must be hospitalized. Dr. Chance says she will die within a week. Anna refuses to change her mind about the lawsuit, however. At the hearing, Sara decides she will represent herself and Brian. Consequently, Brian takes Anna to stay with him at the fire station to give Anna some distance from her mother. He believes if they remain in the same house together, Anna may unwillingly cave to her mother’s wish that she donate her kidney. Meanwhile, through flashbacks Campbell and Julia alternately recall scenes from their high-school relationship. They both attend a prep school populated by children from wealthy families. Julia feels and acts like the outsider, and Campbell falls in love with her despite the reservations of his friends and parents. Their relationship ends abruptly, however, when Campbell breaks it off without explanation. In the present, Campbell and Julia initially bicker with each other, but they end up sleeping together the night before the trial begins.
At the trial, both Sara and Campbell question witnesses, including one of the doctors familiar with Kate’s medical history, and both are effective at different times. Reluctantly, Anna takes the stand and admits that she filed the lawsuit because Kate told her to. At the very moment she makes this announcement, Campbell has an epileptic seizure and collapses. When his seizure ends, he admits he has been having seizures ever since a car accident in high school. He broke up with Julia because he didn’t want his seizures, which limit him greatly, to limit Julia as well. He also explains that the seizures are the reason he has a service dog, which can tell when another seizure is coming on. Julia and Campbell reconcile. Back on the stand, Anna explains that Kate asked Anna not to donate her kidney because she was tired of being sick and waiting to die. Anna also admits that while she loves her sister, part of her wanted Kate to die, too, so that she could have more freedom with her life. Judge DeSalvo decides to grant Anna medical emancipation and gives Campbell medical power of attorney over her.
On the way to the hospital, Campbell and Anna get into a serious car accident. At the hospital, the doctors tell the family that Anna has irreversible brain damage. Campbell tells the doctors to give Anna’s kidney to Kate. Kate narrates the epilogue, set in 2010. She discusses the grief her family went through after Anna’s death, and the fact that she blames herself. She knows, however, that she will always carry Anna with her.