It was created after the success of three one-hour documentaries produced by creator Alan Landsburg: In Search of Ancient Astronauts in 1973 (based on the 1968 book/ 1970 film Chariots of the Gods?

by Erich von Däniken), In Search of Ancient Mysteries (1974), and The Outer Space Connection in 1975 (later adapted into popular paperbacks written by Landsburg), all of which featured narration by Rod Serling, who was the initial choice to host the spin-off show.

Each episode of the program explored a general or specific topic in one of several general categories as given in the opening titles: Extraterrestrials, Magic & Witchcraft, Missing Persons, Myths & Monsters, Lost Civilizations, and Special Phenomena (changed to Strange Phenomena from season 3 onward).

Additionally, it featured episodes about mysterious historical events and personalities such as Anna Anderson, the Lincoln Assassination, the Jack the Ripper murders, infamous cults (e.g., Jim Jones), and missing persons, cities, and ships (e.g., Amelia Earhart, Jimmy Hoffa, D. B. Cooper, the Mary Celeste, the Titanic, the lost Roanoke Colony).

[5] As part of his research, Nimoy found records in the archives of the hospital where Van Gogh was treated that suggested that he suffered from epilepsy rather than insanity.

[6] In 1978, Landsburg produced a Bigfoot documentary using portions of two In Search of... episodes ("The Monster Hunters" and "The Yeti") called Manbeast!

Anastasia: An examination of evidence that the youngest daughter of Russia's Tsar Nicholas II Aleksandrovich Romanov survived the family executions, and settled in Charlottesville, Virginia.

Angel of Death: Nazi hunter Simon Wiesenthal tracks infamous war criminal Josef Mengele to his hiding place in Paraguay.

[21] In February 2012, it was announced that Visual Entertainment, under license from Universal Studios, had acquired the home video rights to the original series for the United States and Canada.

Two other examples are Truth from Legend and Fact from Myth, two nearly identical series existing in alternate universes for which "mini-episodes" were created for YouTube as part of the viral marketing campaign for the two-part video game BioShock Infinite: Burial at Sea.