The program's heyday was in the early 1950s, when radio actor, producer and director Elliott Lewis took over (still during the Wilcox/Autolite run). Here the material reached new levels of sophistication. The writing was taut, and the casting, which had always been a strong point of the series (featuring such film stars as Orson Welles, Joseph Cotten, Henry Fonda, Humphrey Bogart, Judy Garland, Ronald Colman, Marlene Dietrich, Eve McVeagh, Lena Horne, and Cary Grant), took an unexpected turn when Lewis expanded the repertory to include many of radio's famous drama and comedy stars — often playing against type — such as Jack Benny. Jim and Marian Jordan of Fibber McGee and Molly were heard in the episode, "Backseat Driver," which originally aired February 3, 1949.

The highest production values enhanced Suspense, and many of the shows retain their power to grip and entertain. At the time he took over Suspense, Lewis was familiar to radio fans for playing Frankie Remley, the wastrel guitar-playing sidekick to Phil Harris in The Phil Harris-Alice Faye Show. On the May 10, 1951 Suspense, Lewis reversed the roles with "Death on My Hands": A bandleader (Harris) is horrified when an autograph-seeking fan accidentally shoots herself and dies in his hotel room, and a vocalist (Faye) tries to help him as the townfolk call for vigilante justice against him.

With the rise of television and the departures of Lewis and Autolite, subsequent producers (Antony Ellis, William N. Robson and others) struggled to maintain the series despite shrinking budgets, the availability of fewer name actors, and listenership decline. To save money, the program frequently used scripts first broadcast by another noteworthy CBS anthology, Escape. In addition to these tales of exotic adventure, Suspense expanded its repertoire to include more science fiction and supernatural content. By the end of its run, the series was remaking scripts from the long-canceled program The Mysterious Traveler. A time travel tale like Robert Arthur's "The Man Who Went Back to Save Lincoln" or a thriller about a death ray-wielding mad scientist would alternate with more run-of-the-mill crime dramas.

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