Suspense went through several major phases, characterized by different hosts, sponsors and director/producers. There were a few rules which were followed for all but a handful of episodes: the protagonist was usually a normal person suddenly dropped into a threatening or bizarre situation; solutions were "withheld until the last possible second"; and evildoers were punished in the end. The program made only occasional forays into science fiction and fantasy. Among its science fiction entries were "The Man who Tried to Save Lincoln" (a time travel fantasy) and an adaptation of Curt Siodmak's Donovan's Brain, as well as an adaptation of an H. P. Lovecraft short story, "The Dunwich Horror".

Alfred Hitchcock directed its audition show (for the CBS summer series Forecast). This was an adaptation of "The Lodger," a story Hitchcock had filmed in 1926 with Ivor Novello. Martin Grams, Jr., author of Suspense: Twenty Years of Thrills and Chills, described the Forecast origin of Suspense:

On the second presentation of July 22, 1940, Forecast offered a mystery/horror show titled Suspense. With the co-operation of his producer Walter Wanger, Alfred Hitchcock received the honor of directing his first radio show for the American public. The condition agreed upon for Hitchcock's appearance was that CBS make a pitch to the listening audience about his and Wanger's latest film, Foreign Correspondent. To add some flavour to the deal, Wanger threw in Edmund Gwenn and Herbert Marshall as part of the package. All three men (including Hitch) would be seen in the upcoming film, which was due for a theatrical release the next month. Both Marshall and Hitchcock decided on the same story to bring to the airwaves, which happened to be a favorite of both of them: Marie Belloc Lowndes' "The Lodger." Alfred Hitchcock had filmed this story for Gainsborough in 1926, and since then it had remained as one of his favorites.

Herbert Marshall portrayed the mysterious lodger, and co-starring with him were Edmund Gwenn and character actress Lurene Tuttle as the rooming-house keepers who start to suspect that their new boarder might be the notorious Jack-the-Ripper. [Gwenn was actually repeating the role taken in the 1926 film by his brother, Arthur Chesney. And Tuttle would work again with Hitchcock nearly 20 years later, playing Mrs. Al Chambers in Psycho.] Character actor Joseph Kearns also had a small part in the drama, and Wilbur Hatch, head musician for CBS Radio at the time, composed and conducted the music specially for the program. Adapting the script to radio was not a great technical challenge for Hitchcock, and he cleverly decided to hold back the ending of the story from the listening audience in order to keep them in suspense themselves. This way, if the audience's curiosity got the better of them, they would write in to the network to find out whether the mysterious lodger was in fact Jack the Ripper. For the next few weeks, hundreds of letters came in from faithful listeners asking how the story ended. Actually a few wrote threats claiming that it was "indecent" and "immoral" to present such a production without giving the solution.