The Lisbons are a Catholic family living in Grosse Pointe, Michigan in the 1970s. The father, Ronald, is a math teacher at a private school and the mother is a homemaker. The family has five daughters: 13-year-old Cecilia, 14-year-old Lux, 15-year-old Bonnie, 16-year-old Mary, and 17-year-old Therese.

Their lives change dramatically within one summer when Cecilia, a stoic and astute girl described as an "outsider", attempts suicide by cutting her wrists. A few weeks later, the girls throw a chaperoned party, during which Cecilia jumps from their second story window and dies, impaled by a fence post.

The cause of Cecilia's suicide and its after-effects on the family are popular subjects of neighborhood gossip. The mystique of the Lisbon girls operates also for the neighborhood boys, the narrators of the novel.

Lux begins a romance with local heartthrob Trip Fontaine. Trip negotiates with the overprotective Mr. and Mrs. Lisbon to take Lux to a homecoming dance, on the condition that he finds dates for the other three girls. After having sex with Trip on the high school football field after the dance, Lux misses her curfew. Consequently, the Lisbons become recluses. Mrs. Lisbon pulls all the girls out of school, claiming that it would help the girls recover from Cecilia's suicide. However, despite her attempt to protect the girls from boys and sex, over the winter, Lux is seen having sex with various unknown men on the roof nightly. A few months after Lux is sent to the hospital because of a pregnancy scare—which her parents were told was simply indigestion—Mr. Lisbon officially takes a leave of absence. Their house falls into a deeper state of disrepair; none of them leave the house and no one visits, not even to deliver milk and groceries. A strange smell coming from the house permeates the neighborhood. From a safe distance, all the people in the neighborhood watch the Lisbons' lives deteriorate, but no one can summon up the courage to intervene.

During this time, the Lisbons become increasingly fascinating to the neighborhood in general and the narrator boys in particular. The boys call the Lisbon girls and communicate by playing records over the telephone for the girls.

Finally, the girls send a message to the boys to come to the house. Shortly after the boys arrive, three of the sisters kill themselves: Bonnie hangs herself, Therese overdoses on sleeping pills, and Lux dies of carbon monoxide poisoning. Mary attempts suicide by putting her head in the oven, but fails. Mary continues to live for another month before successfully ending her life by taking sleeping pills. Newspaper writer Linda Perl notes that the suicides come a year after Cecilia's first attempt. After the suicide "free-for-all," Mr. and Mrs. Lisbon leave the neighborhood. The house is sold to a young couple from the Boston area and most of the Lisbons' personal effects are either thrown out or sold in a garage sale. The narrators scavenge through the trash to collect much of the "evidence" they mention. The boys that once loved them from afar are now grown men, determined to understand a tragedy that has always defied explanation. For still, the question remains – why did all five of the Lisbon girls take their own lives?