House of Mystery was originally published by National/DC Comics in December 1951 as a horror anthology, featuring weird tales of the supernatural or mystery-themed stories. However, Dr. Fredric Wertham’s Seduction of the Innocent crusade led to a growing backlash against similar horror comics in the mid-1950s, and the advent of the "Comics Code Authority" with its restrictions on horror-themed story lines (banning stories dealing with such fare as werewolves, vampires, etc.), so the series was revamped as a science-fiction adventure series, with those monster and other mystery-suspense type tales that were permitted by the comics code.
Beginning in the mid-1960s, the book was taken over by super-hero stories headlining the Martian Manhunter (House of Mystery #143; June 1964) and the introduction of Dial H for Hero (House of Mystery #156; January, 1966).
The title once again changed format beginning with issue #174, when EC Comics veteran Joe Orlando was hired by DC to take over as editor. As the Comics Code Authority provisions were being challenged at that time by both DC and Marvel over its content restrictions, Orlando wisely chose to return the series to its original horror themes. The first issue under Orlando reprinted old horror/suspense stories, but the new direction truly began with House of Mystery #175 (May-June 1968) which introduced Cain, the "care taker" of the House of Mystery, who would introduce nearly all stories that would run in the series before its cancellation in October 1983. Cain also hosted the spin-off series Plop! and became a recurring character in Neil Gaiman’s The Sandman.