During the opening credits, the camera slowly pans over the myriad medications for Marvin (Hume Cronyn), the elderly, bedridden invalid cared for round-the-clock by his daughter, Bessie (Diane Keaton). The film opens with Bessie visiting Dr. Wally (Robert DeNiro), a pathologist cum primary care physician, for diagnostic tests which show that she has leukemia.

Bessie also takes care of her Aunt Ruth, whose electric unit for pain relief and penchant for soap operas provide comic relief in this bittersweet drama about families and responsibilities. Because Bessie's best chance for survival is a bone marrow transplant, she contacts her sister, Lee (Meryl Streep), estranged since their father's first stroke and Lee's decision not to help care for him.

Lee's oldest son, Hank (Leonardo DiCaprio), is a troubled seventeen-year-old who sets fire to their home and is hospitalized in a mental institution. Released for this special trip to visit his Aunt Bessie, Hank continues his rebellion by refusing to be tested as a possible donor. Lee is a dysfunctional mother: she does not respond to her son's apology regarding the arson, she has her younger son light cigarettes, and she confuses discipline with control.

The family unites in and around Marvin's room. Reunions are never as smooth as planned, and tensions, stored bitterness, and anger erupt. The sisters confront each other in their failures as sisters--Bessie had never contacted her nephews in any way and Lee had never looked back. But through it all, love and caring emerge: the sisters come to a new understanding, Bessie's reaching out to rebellious Hank is reciprocated, and Lee even learns to communicate caring to her son.