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It was hosted by Leonard Nimoy. The series conducts "investigations" into the pseudoscientific and paranormal (e.g., UFOs, Bigfoot, and the Loch Ness Monster). Additionally, it features episodes about mysterious historical events and personalities such as Anna Anderson/Grand Duchess Anastasia, 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). Because the show often presents offbeat subjects and controversial theories, each episode's opening credits include a verbal disclaimer about the potentially conjecturable nature of the evidence and theories to be presented:

"This series presents information based in part on theory and conjecture. The producer's purpose is to suggest some possible explanations, but not necessarily the only ones, to the mysteries we will examine."

The production values were fairly typical of the period, with the interviews, reenactments and scene footage all shot on film and usually voiced over by Nimoy. The style was often more expository than explanatory, although the music, composed by Rinder and Lewis, was particularly effective in creating an aura of mystery and suspense.

Nimoy's popularity among science fiction fans (due to his role in the Star Trek television series) won the show a following in fandom circles. Nimoy wrote a particularly fascinating episode of the show dealing with the turbulent life of artist Vincent van Gogh. Nimoy had played van Gogh's brother in a one-man show and set out to find out the truth about the life of the great artist. Many have said that van Gogh was insane, but Nimoy discovered evidence that he actually suffered from epilepsy. He delivered a very touching monologue at the end of the show about Theo van Gogh's final moments with his brother Vincent.

The show also spawned at least six spin-off books: In Search of Lost Civilizations, In Search of Extraterrestrials, In Search of Magic and Witchcraft, In Search of Strange Phenomena, In Search of Missing Persons, and In Search of Myths and Monsters with an additional book that collected the best segments from these existing tomes.

The In Search Of series aired during the early 1990s on the A&E Network, which edited out all of Leonard Nimoy's on-camera appearances. In the latter 1990s, the show aired on another of the A&E Television Networks' properties, The History Channel, which included Leonard Nimoy's on-camera appearances. The licensing agreement expired in the early 2000s, ending the show's run.

A short-lived revival of the show, featuring Mitch Pileggi, aired on the Sci-Fi Channel in 2002.

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