Cecil B. DeMille was the host of the series each Monday evening from June 1, 1936, until January 22, 1945. On several occasions,usually when he was out of town, he was temporarily replaced by various celebrities, including Leslie Howard and Edward Arnold.

It was a clash over closed shop union rulings favoured by the old American Federation of Radio Artists that ended DeMille's term as Lux Radio Theater's host. AFRA assessed members a dollar each to help back a campaign to enact closed-shop rulings in California. DeMille, an AFRA member but a stern opponent of closed shops, refused to pay because he believed it would nullify his opposition vote. When AFRA ruled those not paying faced suspension from the union, and thus a ban from appearing on the air, DeMille was finished in radio---because he also refused to let anyone else pay the dollar for him (In his 1959 autobiography, DeMille alleged that a former member of the American Communist Party later confided to him that the party had consciously orchestrated these circumstances of his exclusion from radio, as they considered him to be one of their two foremost enemies in radio). Lux Radio Theater auditioned, on the air, several hosts over the next year, until they settled on William Keighley as the new permanent host, a post he held from late 1945 through mid-1955.