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"The Family Guy" is about the adventures of Peter Griffin, a bumbling but well-intentioned blue-collar worker. Peter is an Irish-American Catholic with a thick Rhode Island / Eastern Massachusetts accent.

During the course of the series, he discovers he is part African-American and has been known to have Spanish, Mexican, Scottish, "Huttish" (fictional species from Star Wars), and German ancestors. He is known for his trademark laugh. His wife Lois, who has a similar accent, is a stay-at-home mum/piano teacher, and is a member of the Pewterschmidt family of wealthy Protestant socialites.

Peter and Lois have three children: teenage daughter Meg Griffin who is frequently the butt of jokes for her ugliness; goofy and unintelligent teenage son Chris Griffin, in some respects a younger version of his father; and diabolically evil infant son Stewie Griffin, bent on world domination and the death of his mother. Stewie speaks fluently and eloquently, with an Upper Class English accent and stereotypical arch-villain phrases.

While other characters can hear and understand Stewie, most of his dialogue is ignored or not taken seriously. Brian (the talking pet dog) is the only character that regularly interacts with Stewie on an intellectual level. Stewie refers to his mother and father as "Lois" and "the fat man" respectively.

Brian is anthropomorphized in that he walks on two legs, drinks Martinis, owns his own car (a Toyota Prius, circa 2004) and engages in human conversation, though he is still considered a pet in many respects.

Occasionally, Brian will act in a stereotypically canine manner, usually for comedic effect (such as his inability to stand up in the back of a car, chasing tennis balls, fear of vacuum cleaners and barking uncontrollably at black people—which he blames on his father's side of the family). He does, however, object to any overly submissive domestic behavior.