The series centers on Ren Höek, a short-tempered, "asthma-hound" Chihuahua, and Stimpson J. "Stimpy" Cat, a 3-year-old dimwitted and happy-go-lucky cat. The duo fill various roles from episode to episode, including outer-space explorers, Old West horse thieves, and nature-show hosts, and are usually at odds with each other in these situations. While the show was sometimes set in the present day, the show's crew tended to avoid "contemporary" jokes about current events. The show extensively features off-color and absurdist humor, and slapstick.
The show features a host of supporting characters. Some appear only in one episode, while others recur and occasionally appear in different roles (like Powdered Toast Man). They may either be part of the storyline, or make cameo appearances with little bearing on the plot. Some, such as Mr. Horse, are exclusively cameo-based, spontaneously appearing as a running gag.