Set in New York City, the film follows three Mozell sisters, who deal with their self-obsessed lives and hang up on others in phone conversations. The eldest sister Georgia (Diane Keaton), age 50, is single and runs a successful women's magazine in NYC. The youngest sister Maddy (Lisa Kudrow), age 34, is also single and a not-very-bright nobody who has just landed her big break as a soap opera actress. Middle child Eve (Meg Ryan), age 39, is an event planner living in Los Angeles with a husband named Joe Marks (Adam Arkin) and their young teenage son Jesse, and spends most of her time worrying that her ailing and cantankerous 79-year-old father, Lou Mozell (Walter Matthau), will die at any minute.
Much of the story proceeds around phone calls the three sisters make to each other (rudely hanging up on each other without saying good-bye), and calls that Lou makes to Eve.
Eve places Lou in the hospital for tests because he has been having memory problems. He recalls his days writing a screenplay with his wife for a John Wayne movie. His wife, the daughters mother, left them in the 1980s because she no longer loved him and felt she did not make it as a mother.
Eve tends to Lou in the hospital, whose senility is becoming more evident. At one point, Lou even comes on to Eve, thinking she is a past love named Cleo.
In a flashback to 11 years ago in 1988, Eve remembers when she and her sisters came to visit Lou for Christmas at his house in L.A., and found him in bed with their female dental hygienist. Afterwords, Lou gets sad and says he misses his wife. Eve goes off to visit her mom Pat (Cloris Leachman), asking her to return to Lou, but she is adamant about her reasons for leaving. She does not care that Lou recently tried to kill himself. Eve returns to their house and goes out with Lou to get a Christmas tree, which cheers him up.
In the present day, Maddy brings a huge St. Bernard dog to visit Eve. Some hilarity ensues.
Meanwhile, Lou wanders out of the hospital back to their old house, and Eve comes to pick him up.
In another flashback to six years earlier, Eve remembers Halloween in 1993. She throws a big costume party for her son Jesse, but Lou shows up drunk and ruins the party. He insults her and she throws him out.
In the present, Lou has a "mini-stroke" as Eve is dealing with planning a speech Georgia will deliver to a women's group. Georgia suggests to Eve (by phone) that Lou should sign a blank check for their needs because he has plenty of money in the bank, but he refuses.
After the mother of a doctor tells Eve that she needs to let go of her estranged mother, Eve goes to Lou and lies that his wife died in an earthquake. He whispers to her, "I won."
Eve gathers up all cell phones in her house and puts them in a cupboard.
Georgia makes a big entrance at the women's event, then makes a surprising and insincere speech about her father dying, leaving her sisters aghast. She concludes that her generation of women are dealing with the death of their parents as they face their own mortality.
Eve gets upset at Georgia and Maddy because she deals with their dad more than them. The three of them then bicker at length. They get a call that Lou has gone into a coma and rush to the hospital.
After more tension between the sisters, Eve tells Georgia that she needed her help.
The sisters sit by Lou's bed as Eve tries yet again to recall the name of a short blonde actress from the 1950s who always played sad roles. Lou becomes conscious for a second and says, "June Allyson." The sisters are thrilled that he is right, but just as suddenly as he spoke, his heart stops beating. A nurse comes in to find he has no pulse, and he dies before their eyes.
In the final scene, some months later at Thanksgiving, the three sisters make turkey, and get into a mild food fight. Eve has another memory of her father, this time dancing with his daughters and wife.