The show revolves around 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 mom/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.
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