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In the early talkie era, Seiter helped nurture the talents of RKO's comedy duo Wheeler & Woolsey in such rollicking features as Caught Plastered (1931) and Diplomaniacs (1933). He also directed the Laurel and Hardy feature Sons of the Desert (1933), their only film together. Other films include Sunny, Going Wild, Kiss Me Again, Hot Saturday, Way Back Home, Girl Crazy, Rafter Romance, Roberta, Room Service, Susannah of the Mounties, Allegheny Uprising, You Were Never Lovelier, Up in Central Park, and One Touch of Venus.

Among the many stars directed by Seiter during his long career were Shirley Temple, Fred Astaire, Ginger Rogers, Henry Fonda, Margaret Sullavan, Jack Haley, Deanna Durbin, Jean Arthur, John Wayne, Fred MacMurray, Lucille Ball, Rita Hayworth and the Marx Brothers.

While many of his films were minor gems, Seiter was capable of turning out bad movies once in a while. For example, if he ran into friction from his star—as was the case with Lou Costello in 1946's Little Giant -- Seiter would get even by adhering religiously to the script, refusing to add any nuance or creativity to the project (this pettiness may have been the reason that one prominent actress of the 1930s referred to Seiter as the most unimaginative director she'd ever worked with). On his final four films, before he retired in 1954, Seiter functioned as both producer and director. These films included The Lady Wants Mink (1953), a gentle satire of the then topical "raise your own coat" craze.

He died in Beverly Hills, California, of a heart attack, aged 74.