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Like Dexter's Laboratory and other Cartoon Network series from the 1990s, the original pilot appeared as an episode of the series What-A-Cartoon!. The Cow and Chicken series first broadcast on Cartoon Network from 1997 to the year 2000, with reruns airing until 2004. Late into the series run, the characters I.M. Weasel and I.R. Baboon, who were part of the series' recurring segment, I Am Weasel, were spun-off onto their own series. Cow and Chicken are sister and brother, a cow and a chicken, but who have human parents. The creators were faced with the question of whether and how to explain this scenario. Sometimes opening credits are cumbersome vehicles for an origin story. David Feiss approached this problem in the series' opening title sequence: Mama had a chicken/Mama had a cow/Dad was proud/He didn't care how. This is all that is ever offered in explanation, though there is one hint in the episode "The Day I Was Born" that Cow is adopted (Chicken's paternity is unknown).

Cow and Chicken's extended family consists of various other types of animals, including Cousin Boneless, who is a boneless chicken (unable to walk or get up from the floor); Snail Boy, a snail; Cousin Black Sheep; and Sow, an evil pig. They also have an uncle Longhorn Steer, who appears in "Professor Longhorn Steer". The episode "Happy Meat" also showed the ghosts of a pair of Cow and Chicken's ancestors, a male farmer and a female chicken.

• Official UK website
• Unofficial Cow and Chicken website
• Cow and Chicken Episode Guide at the Big Cartoon DataBase