The novel focuses on a young adult male, Jacob Hunt, with Asperger's syndrome living in Townshend, Vermont,[1] who is accused of murder.

The novel follows the struggle between Jacob and his family (consisting of his mother, Emma, and his younger brother, Theo), the law, and his disability.

House Rules is told through the perspective of five character voices, including, Emma, Theo, Jacob, Rich, and Oliver.

Picoult frequently uses this narrative technique in her novels, including in, My Sister's Keeper, Songs of the Humpback Whale, Change of Heart, Sing You Home, and Handle with Care.

The novel contains short discussions of murder(s) committed by real murderers, including: Ted Bundy, Richard Crafts, Christopher Hightower, Darryl Littlejohn, Jeffrey MacDonald, Stella Nickell, Dorothea Puente, Dennis Rader, Gary Ridgway, and Bill Sybers.