The show is set in the fictional city of Quahog, Rhode Island.

Quahog was founded by Griffin Peterson, who had been exiled to America by King Stewart III in "Peter's Progress". The king later gave Peterson control over Quahog after Peterson beat him in a talent show. A myth was later created that said that Quahog was founded by Miles "Chatterbox" Musket with the assistance of a magical talking clam.

Voiced by the actor of the same name, Mayor Adam West once married his right hand and at one point thought his name was "Adam We" when pieces were missing from his Lite-Brite.

Stewie, equipped with his teddy bear and his laser gun, has, on several occasions, almost single handedly taken over the world.

In "Padre de Familia", it is revealed that Peter was born in Mexico, where his mother had tried unsuccessfully to abort him.

Although he is mentally challenged and a ward of the state, Opie has won "Employee of the Month" at least twenty times.

Stewie is constantly plotting ways to kill his mother, apparently holding a grudge against her because of his nine-month stay in her "ovarian Bastille."

After experimenting with the mainstream religions, Peter's father tells him to look into his heart, which results in the creation of Fonzism, a religion devoted to Fonzie. Peter converts his shed into The First United Church of the Fonz. While successful at first, Sherman Hemsley comes to convert people to a religion devoted to George Jefferson, and Kirk Cameron converts the rest back to Christianity.

In "Brian Sings and Swings", he tells Lois, "Remember what I always tell you, if I come home in the middle of the day and catch you having sex with someone, I'll kill you both." But when he catches her in bed with Bill Clinton in "Bill and Peter's Bogus Journey", he takes no hostile actions whatsoever.

The Drunken Clam, often shortened to just The Clam, is the local Quahog bar owned by Jerome and formerly Horace. Many of Peter's adventures are hatched or even take place in the Clam.