My Sister's Keeper is the story of the Fitzgerald family. Kate Fitzgerald was discovered to have acute promyelocytic leukemia, when still a toddler. Sara and Brian conceived a third child (they already had a son, Jesse), Anna, to be a perfect genetic match for her sister; Anna's cord blood was donated to Kate, but it was not enough.

The film picks up when Anna is thirteen. Kate is ill again, and Fitzgerald parents plan to have Anna donate her kidney to Kate. Anna decides to sue for emancipation, and the choice to choose for herself what body parts she donates. Anna hires lawyer Campbell Alexander and goes to court against her own mother, a former lawyer herself, who decides to represent the rest of the family.

A further subplot concerns the relationship between Campbell and Anna's guardian ad litem, Julia Romano.

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