Gaines was the son of Max Gaines, publisher of the All-American Comics division of DC Comics and also an influential figure in the history of comics, having tested the idea of selling comics on newsstands, inspiring the creation of Wonder Woman among other achievements.
William Gaines became publisher of a small comics publisher called Educational Comics, or EC for short. The company published Bible comics and other educational fare. Gaines changed the name to Entertaining Comics and began searching for a niche among the dozens of comic book publishers who flourished at that time.
He found his niche in publishing horror, science fiction and fantasy comics, as well as realistic war comics, and the legendary MAD and Panic satire comics. His books, including Tales From The Crypt, Vault of Horror, Shock SuspenStories, Weird Science and Two Fisted Tales featured stories with content above the level of the typical comic.
His horror comics were not simply compilations of horrifying visuals, but subtle, satiric approaches to horror with genuine dilemmas and startling outcomes, along with horrifying visual graphics, to be sure, often with stories drawn from classic authors, such as Edgar Allan Poe and H. P. Lovecraft. Likewise, his science fiction and fantasy titles dealt with adult issues like racism and the meaning of progress and had stories by, among others, Ray Bradbury. The books also featured artists who came to be among the most prominent commercial illustrators of the 20th century, among them Wallace Wood, Jack Davis, and Bill Elder.
MAD was also first a comic book satirizing other comic books. It was so popular that dozens of imitations were published, including EC's own Panic.
Gaines's comics may have appealed to adults, but comic books were considered by the general public to be aimed at children. With the publication of Dr. Frederic Wertham's Seduction of the Innocent, comic books in the Gaines style drew the attention of the U.S. Congress and the moralizing classes in general and EC was effectively driven out of business by the Comics Magazine Association of America, an industry group that he had suggested, but lost control of to John Goldwater publisher of the innocuous Archie teenage comics. See Comics Code.
Gaines converted MAD to a magazine to escape the strictures of the comics code (not to mention that he had run out of comic books to satirize) and went on to a long career as a publisher of satire and enemy of bombast.