Margot (Nicole Kidman) is a successful but neurotic writer who brings her 11-year-old son Claude (Zane Pais) to spend a weekend visiting her free-spirited sister Pauline (Jennifer Jason Leigh) on the eve of her wedding to Malcolm (Jack Black) at Pauline & Malcolm's home on Long Island. Margot disapproves of Pauline's choice of fiancĂŠ, which will become one of several sources of tension between the two sisters. Malcolm is also free-spirited, but also unsuccessful, unmotivated, socially inappropriate and "completely unattractive". Because much of Malcolm's time is spent dabbling in painting, playing music and writing letters to magazines, Margot feels that Pauline could do better. While in town, Margot will also be interviewed in a local bookstore by Dick Koosman (CiarĂĄn Hinds), a successful author with whom Margot is collaborating on a screenplay. Dick's teenage daughter Maisie (Halley Feiffer) also visits the house.
Although Pauline is happy that Margot showed up, the two share a wellspring of tension. Margot disapproves of Pauline's life-choices - besides marrying Malcolm, Pauline is pregnant, a fact that she hasn't shared with Malcolm or her pre-teenage daughter Ingrid. Pauline resents how her life experiences have been used in Margot's writing. She is also incensed when Margot shares secrets told to her in confidence - including her pregnancy. Each of the sisters feels unfairly picked on by the other. Rather than take their frustrations out on each other, the sisters target those around them. Pauline twits her fiancĂŠ's sense of inadequacy. Margot skewers her son's physical and emotional awkwardness. As he grows up, Claude becomes more of a target of her merciless powers of observation.
Tensions come to a head twice. Margot's interview goes disastrously wrong when Dick's questions become personal. While Pauline interrogates him about emails he received from one of her 20-year-old students, Malcolm admits he kissed Maisie. Returning to the house, Pauline finds Maisie inside. Though Pauline says nothing, it's obvious to Maisie that Pauline knows the truth. Learning of Malcolm's inappropriate behavior with Maisie, Dick angrily beats Malcolm. After that Pauline and Ingrid escape Malcolm and the house with Margot and Claude.
Fleeing to a motel, Pauline angrily confronts Margot about how her life has been used in Margot's writing. The next day, as Margot advises her to finish her relationship with Malcolm, Pauline calls him. His misery keeps her from rejecting him outright, though it's not clear that she will abandon him.
Margot decides to stay with her sister, even as she sends Claude by bus to Vermont, to live with his father. As the bus pulls away with Claude, Margot has a change of heart and chases after it. Taking a seat next to a surprised Claude, Margot catches her breath.

Question: Which sister is neurotic?
Answer: Margot.
Alternative answer: Margot