Nat drives on the interstate with his two young daughters in the back seats, when a car drives by and an unknown guy shoots one of his daughters dead for no reason. Nat's life is shattered. He becomes obsessed with finding the killers, assaults two men, kills one, goes to jail, is left by his wife, grows old estranged from his other daughter. We see the action first through Nat's eyes, then via Brautigan, the cop in charge of the investigation, and finally from the perspective of the remaining daughter Margo. The deconstructed narrative echoes the chaos within Nat and emphasizes the fact that the characters are out of tune with one another, which is the meaning of the original title.

Simon Birch and Joe Wenteworth are boys who have a reputation for being oddballs. Joe never knew his father, and his mother, Rebecca, is keeping her lips sealed no matter how much he protests. Simon, meanwhile, is an 11-year-old dwarf whose outsize personality belies his small stature. Indeed, he often assails the local reverend with thorny theological questions and joins Joe on his quest to find his biological father.