The novel takes place in Three Rivers, Connecticut. Dominick Birdsey's identical twin, Thomas, suffers from paranoid schizophrenia. With medication, he can function properly and work at a coffee stand, but occasionally he has severe episodes of his illness. Thinking he is making a sacrificial protest that will stop the war in the Middle East, Thomas cuts off his own hand in a public library. Dominick sees him through the ensuing decision not to attempt to reattach the hand, and makes efforts on his behalf to free him from what he knows to be an inadequate and depressing hospital for the dangerously mentally ill.
In the process, Dominick reviews his own difficult life as Thomas's normal brother, his marriage to his gorgeous ex-wife, which ended after their only child died of SIDS, and his ongoing hostility toward his stepfather. Dominick also displays classic symptoms of PTSD, as a result of stressors in his adult life. First in Thomas's interests, and then for his own sake, he sees a therapist, Dr. Rubina Patel, an Indian psychologist, employed by the hospital. She helps Dominick come to understand Thomas's illness better and the family's accommodations or reactions to it.
In the course of Thomas's treatment, Dominick is covertly informed of sexual abuse taking place in the hospital, and helps to expose the perpetrators. He succeeds in getting Thomas released, but Thomas soon dies, apparently by suicide. After Thomas's death, Dominick discovers the identity of their birth father, who was part African American and part Native American—a secret their mother had shared with Thomas, but not with him.
In the midst of this, Dominick is also reading the autobiography of his grandfather, Italian/Sicilian-born Domenico Tempesta, which discloses details about the legacy of twins in their family. Dominick learns about himself and his mother through learning about his grandfather.
He also learns that his live-in girlfriend, Joy, has been seeing a gentleman on the side, who is her bisexual half-uncle, and has also let him watch her and Dominick during sex on previous occasions. She is also HIV-positive, having contracted it from said secret lover. She asks Dominick to raise her baby if she dies. At first he resists, but later, after having found his way back into a relationship with his ex-wife, Dessa, they decide to remarry each other and adopt Joy's daughter. The book ends with Dominick able to cope with the considerable loss, failure, and sorrow in his personal and family history.