The Shadow came to network airwaves on September 26, 1937, over the new Mutual Broadcasting System. Thus began the "official" radio drama that many Shadow fans know and love, with 22-year-old Orson Welles starring as Lamont Cranston, a "wealthy young man about town." Once The Shadow joined Mutual as a half-hour series on Sunday evenings, the program did not leave the air until December 26, 1954.

Orson Welles did not speak the signature line of "Who knows what evil lurks in the hearts of men?". Instead, radio veteran Frank Readick, Jr. (who had played the The Shadow in an earlier radio series) did, using a water glass next to his mouth for the echo effect. The famous catch phrase was accompanied by the strains of an excerpt from Opus 31 of the Camille Saint-Saëns classical composition, Le Rouet d'Omphale.

After Welles departed the show in 1938, Bill Johnstone was chosen to replace him and voiced the character for five seasons. Following Johnstone's departure, The Shadow was portrayed by such actors as Bret Morrison (the longest tenure, with 10 years in two separate runs), John Archer, and Steve Courtleigh.

The Shadow also inspired another radio hit, The Whistler, with a similarly mysterious protagonist.

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