The "Angels", three investigative agents (Barrymore, Diaz and Liu) who work for the Charles Townsend Detective Agency, return for another high-octane series of adventures as they investigate the theft of a database of witness protection profiles, after five of the people on the list are murdered.

They’re aided by a new Bosley (Bernie Mac), in an adventure which pits them against a "fallen angel" (Moore), their old nemesis, the Thin Man (Glover), and others.