The Ren and Stimpy Show premiered on Nickelodeon on Sunday, August 11, 1991, and was the third of the three original Nicktoons (Doug and Rugrats having debuted earlier the same day). The show aired new episodes on the channel from 1991 to 1996. The Ren and Stimpy Show had a reputation for indecent humor. The controversy was mainly a result of imagery and violence as well as language and sex references. Episode names included “Stimpy’s First Fart.” In 1992, MTV Networks dismissed Kricfalusi and production moved from Kricfalusi's Spümcø studios to Games Animation, where it stayed until its cancellation for Nickelodeon in 1996. Reruns are broadcast currently by Nickelodeon Canada, Australia and Nicktoons. The show had 3 "banned" episodes by the Nickelodeon censors. "Man's Best Friend" (later appears in Ren & Stimpy "Adult Party Cartoon" cartoon), "Sammy and Me" (banned for the part where Stimpy gouges his eye out to insert a fake eye), and "The Last Temptation of Ren" (banned because it was to air with "Sammy and Me"). These episodes aired on MTV in later years.

Ren Höek is an Asthma hound Chihuahua. Martin "Dr. Toon" Goodman of Animation World Magazine described Ren as "scrawny," "dyspeptic", and "violently psychotic."

Kricfalusi originally voiced Ren, using what he described as "a bad imitation of Peter Lorre" 53[dead link]. When Nickelodeon fired Kricfalusi, Billy West, already the voice of Stimpy, took the role using a combination of Burl Ives, Kirk Douglas, and a slight "south of the border accent" for the rest of the Nickelodeon run. Kricfalusi returned to the voice for the Nickelodeon series and Ren & Stimpy "Adult Party Cartoon" on Spike TV.

Stimpson "Stimpy" J. Cat is a three year old, fat, untailed, red and white Manx cat with a blue nose, purple eyelids, human-style buttocks, and flat feet. Martin "Dr. Toon" Goodman of Animation World Magazine described Stimpy as "obese", and "brain-damaged." West voiced Stimpy for the Spümcø and Games Animation episodes, basing the voice on an "amped-up" Larry Fine. Eric Bauza portrayed the character in Adult Party Cartoon.

The show features a host of supporting characters; some are recurring characters while others make single episode appearances. Ren and Stimpy are the only characters to appear in every episode except the episode "Fued for sale"., sometimes as various different pseudonyms, such as "Robin Höek" (a play on Robin Hood). Some of the supporting characters factor directly into the storyline (such as George Liquor) while others make brief cameos. Other characters, such as Mr. Horse, are exclusively cameo-based, appearing in many episodes in bits that have little bearing on the plot as a running gag.

In a 1993 interview, Bill Wray stated that he believed Kricfalusi created the Ren and Stimpy characters around 15 years prior, for Kricfalusi's personal amusement during his years in Sheridan College in Canada. According to commentary in the DVD box set of the show's first two seasons, Kricfalusi was inspired by a 1946 photograph called "New York City, 1946" of a chihuahua in a sweater by Elliott Erwitt on a postcard to create Ren. Kricfalusi combined the two cats in Bob Clampett's "A Gruesome Twosome" (1945) short to create Stimpy with the Jimmy Durante cat's coloring and nose and the stupid one's girth and personality.[citation needed] Wray said that he had initially "forgotten about" the characters. When Nickelodeon requested new series, Kricfalusi assembled a presentation called "Our Gang", similar to a children's show with a live action host presenting various cartoons. Each cartoon parodied a genre, and Ren and Stimpy parodied the "cat and dog" genre. Vanessa Coffey, the producer of the show, said that she did not like the general idea but that she liked Ren and Stimpy.

In 1989, Kricfalusi pitched and sold The Ren and Stimpy Show to Nickelodeon. Kricfalusi's own animation house, Spümcø, finished the pilot in October 1990 and the first episode of the show properly aired on August 11, 1991, premiering alongside Doug and Rugrats. Spümcø continued to produce the show for the next two years while encountering issues with Nickelodeon standards and practices. Over the years a number of episodes were censored.

According to West, at one point Nickelodeon considered him for the voice of Ren. Spümcø says that Nickelodeon did not consider him for the part.

Kricfalusi described Nickelodeon in the earliest period as being "simple" as there was one executive; Kricfalusi said that he got along with her. Kricfalusi said that another executive, who came at a later period, tried to can some of the Ren and Stimpy episodes produced. According to Kricfalusi the episodes stayed intact since Kricfalusi did a "trade" with the executive he liked; he would have some "really crazy" episodes in exchange for some "heart-warming" episodes.

Wray stated that on some occasions Kricfalusi completed an episode in eight months, and on some occasions he completed an episode in "two or three" months. Wray described Kricfalusi's ideal production period per episode as four half-hour cartoons per year and added that the arrangement would not "jibe with our production schedule."