John Kricfalusi created Ren and Stimpy in 1978 for personal amusement while studying at Sheridan College, long before pitching the show to Nickelodeon.

Ren was inspired by an Elliott Erwitt photograph titled 'New York City, Circa 1950' showing a sweatered chihuahua at a woman's feet, while Stimpy's design was inspired by the big-nosed cat duo in the 1945 Merrie Melodies cartoon A Gruesome Twosome.

When Nickelodeon approached Kricfalusi for show ideas, he pitched a variety show called 'Your Gang or Our Gang' where Ren and Stimpy were merely pets doing Tom and Jerry-style cartoons, but executive Vanessa Coffey liked the duo so much she gave them their own series instead.

Kricfalusi's contract was terminated by Nickelodeon in September 1992, largely due to production delays and conflicts over the episode 'Man's Best Friend,' which depicted an abusive father figure and which Kricfalusi cites as the primary reason for his firing.

Kricfalusi originally voiced Ren himself, styling the character after a demented Peter Lorre from The Maltese Falcon; after his firing, Billy West (already the voice of Stimpy) took over as Ren using a mix of Burl Ives, Kirk Douglas, and a slight accent.

Musician Frank Zappa voiced an incidental character on the show, marking his final public performance before his death.

Since no toy company wanted to make merchandise for the show, its early lack of merchandising was considered a unique and radical aspect of the series.

The banned episode 'Man's Best Friend,' which neither Nickelodeon nor MTV would air, later resurfaced as the unofficial pilot for the 2003 adult reboot Ren & Stimpy 'Adult Party Cartoon,' airing with a TV-MA rating.

Billy West refused to participate in the 2003 adult reboot because he didn't find it funny and feared it would damage his career, so Eric Bauza replaced him as the voice of Stimpy while Kricfalusi reprised Ren and Mr. Horse.

The show's opening theme 'Dog Pound Hop' was performed by a group of Spümcø employees under the band name 'Die Screaming Leiderhôsens.'

The Ren & Stimpy Show influenced two short-lived imitators, Hanna-Barbera's 2 Stupid Dogs (to which Kricfalusi contributed jokes) and Disney's The Shnookums & Meat Funny Cartoon Show, and Mike Judge credited its MTV reruns with paving the way for Beavis and Butt-Head to be greenlit.

A 1993 two-year deal between Nickelodeon and 20th Century Fox considered Ren & Stimpy for a feature film alongside Rugrats and Doug, but the show's cynical, gross-out humor was deemed a poor fit for a conventional family film, and no Ren & Stimpy movie was ever produced.