The story takes place in affluent suburb of Grosse Pointe, Michigan in 1974, as four neighborhood boys reflect on their neighbors, the five Lisbon sisters. Strictly unattainable due to their overprotective, authoritarian, and fiercely religious, isolating parents, Ronald (James Woods) and Sara (Kathleen Turner). The five blond sisters makes up of Therese (Leslie Hayman), Mary (A.J. Cook), Bonnie (Chelse Swain), Lux (Kirsten Dunst), and Cecilia Lisbon (Hanna R. Hall) whom are the enigmas that fill the boys' dreams.
The film begins with the suicide attempt of the youngest sister, 13-year-old Cecilia, and the immediate aftermath. During a chaperoned party that summer intended to make Cecilia feel better from her apparent depression and seemingly detachment from society and life in general (the film opens with Cecilia laying in a bathtub filled with water, blood colored from slitting her wrists) Cecilia excuses herself mid-party and finally succeeds in taking her life by jumping out of her bedroom window and impaling herself on an iron fence. In the wake of her act, the Lisbon family isolate themselves even more within their community, heightening the sense of mystery about them.
The new school year starts that fall and 18-year-old Lux forms a secret relationship with Trip Fontaine (Josh Hartnett), the school heartthrob. Trip eventually persuades his friend, to allow him to take Lux to the Homecoming dance by promising to find dates for the other sisters and go as a group while Mr. Lisbon volunteers to be one of the chaperones to the dance. After being crowned Homecoming King and Queen, Lux has sex with Trip on the football field that night. Trip abandons her immediately afterwards and never speaks to her again.
Having broken curfew, and for having premarial sex, Lux and the rest of the sisters are punished by a furious Sara by being taken out of school. Sara and Ronald force Lux to burn all of her rock 'n' roll albums and has them sequestered within their house indefinitely. Unable to leave their home, the Lisbon sisters contact the boys using light signals at night as morse code, and share songs over the phone as a means of communicating their emotions back and forth since Sara and Ronald are monitoring their phone calls. Mr. and Mrs. Lisbon further isolate their four daughters from the outside world by refusing them visitors, even from social workers and school officals whom drop by to hand them schoolwork which further heightens the neighborhood mystery about what the Lisbon family is really about.
During this time, Lux begins to have anonymous sexual encounters on the roof of the house late at night, while the boys watch from across the street wondering who the mystery man that Lux is meeting. Finally, after several months of solidary confinement, the Lisbon girls signal for the boys to come over one night presumably to help them escape from the house while their parents are asleep. When the boys arrive, they find Lux sitting alone in the dark living room and smoking a cigarette. She invites them inside to wait for her sisters, while she herself goes to wait in the car.
After waiting several minutes in the dark living room where Lux does not return, the boys wander into the basement looking for her and discover a body hanging from the ceiling. Terrified, they rush back out of the basement and in the process, they stumble across the bodies of the four remaining Lisbon sisters, who had all killed themselves in an apparent suicide pact minutes earlier: Therese took sleeping pills; Bonnie hanged herself in the basement; Mary stuck her head in the gas oven; and Lux died of carbon monoxide poisoning by leaving the car engine running in the garage. The four boys flee from the house.
Devastated by the suicides of all their children, Ronald and Sara quietly flee from the neighborhood a few nights later in the dead of night, never to return. The Lisbon house is sold soon after to a young family from Boston, along with all the house furniture and their personal belongings that Ronald and Sara left behind. Ronald and Sara were never seen or heard of again and the mystery to what happened to them lingers throughout the neighborhood. Though the adults in the community go about their lives as if nothing important really happened, the five dead girls remain a source of mystery and grief for the boys, who cannot forget them to this very day.