The series focuses on an eccentric motley crew that is the Smith family and their three housemates: Father, husband, and breadwinner Stan Smith; his better half housewife, Francine Smith; their college-aged daughter, Hayley Smith; and their high-school-aged son, Steve Smith. Outside of the Smith family, there are three additional main characters, including Hayley's boyfriend turned husband, Jeff Fischer; the family's man-in-a-goldfish-body pet, Klaus; and most notably the family's zany alien, Roger, who is "full of masquerades, brazenness, and shocking antics."

Seth MacFarlaneas Stan Smith / Roger (voice)
Wendy Schaalas Francine Smith (voice)
Rachael MacFarlaneas Hayley Smith (voice)
Scott Grimesas Steve Smith (voice)
Dee Bradley Bakeras Klaus (voice)
Jeff Fischeras Jeff Fischer (voice)
Stephen Colbertas Dr. Dandliker - Dentist (voice)
Carmen Electraas Lisa Silver (voice)
Peter Gravesas Mr. Pibb (voice)
Seth Rogenas Student (voice)
Teresa Hsiao
Nic Wegener
Chris McKenna
Nahnatchka Khan
Judah Miller
Erik Sommers
Mike Barker
Murray Miller
Alan Freedland
Michael Shipley
Alan R. Cohen
Etan Cohen
Carter Bays
Craig Thomas
Seth MacFarlane
Lesley Wake Webster
David Hemingson
Abel Tesfaye