Hillard (Hilly) Wise gives the novel first-person narration. Wise Men is broken into three sections: 1947–52, during Hilly's adolescence; 1972; and the present.
Hilly grows up in New Haven, Connecticut, where the Wises are Jewish in a non-Gentile community. Arthur Wise, Hilly's father, is an ambulance chaser who becomes very wealthy from class-action lawsuits involving airplane crashes.