The names most commonly associated with vaudeville are B.F. Keith, Edward Albee, and Tony Pastor. These were the originators of big-time vaudeville, the cleaner and relatively family-friendly performance form of the late nineteenth and early twentieth centuries, and the place where blackface minstrelsy would find a new home on stage and in animation. Both Keith and Pastor got their start working for American showman P.T. Barnum, and Pastor worked in both blackface minstrelsy and burlesque before building a first-run vaudeville business in New York. Pastor began the shift from male-oriented burlesques to more broadly acceptable minstrel and variety shows in the late 1860s, and by the 1880s was well established. The much younger Keith eventually teamed up with Albee to form the Keith-Albee circuit, which began in Boston, but spread throughout the United States and Canada. Keith-Albee even featured motion pictures in their New York Union Square theatre as early as 1896. Benjamin Franklin Keith and Edward Franklin Albee became partners in the late 1880s, offering audiences "polite" vaudeville. They began producing this "high-class" vaudeville by running continuous shows that were meant to appeal to women and children as well as men, and to middle-class as well as working-class audiences. They advertised, and often delivered, shows in which crude remarks and bawdy costumes were forbidden and even tried to police the behavior of their audiences. In 1906, Keith and Albee extended their influence over big-time vaudeville when they established the United Booking Office, which centralized and regulated hiring for all of their theatres. In the 1920s, Keith-Albee merged with a western chain of vaudeville houses to form the Keith-Albee Orpheum Circuit.

Though Pastor, Keith, and Albee are usually remembered as the originators of vaudeville, they were far from alone. At the height of vaudeville's popularity, small towns might have their own houses and larger regional towns and cities might have houses operated by lesser vaudeville circuits. Of note, for instance, were the theatres of F. F. Proctor, whose East Coast operation Keith-Albee bought in 1906, or those of the impresario Martin Beck, whose Palace Theatre in New York, eventually hired a would-be animator named Dave Fleischer as an usher, and which also became part of the Keith Orpheum circuit.

In 1928, Keith-Albee Orpheum merged with Radio Corporation of America (RCA) to form the Radio-Keith-Orpheum Studio (RKO), which eventually bought he Paul Terry and Amedee Van Beuren animation studios, and for a time distributed the cartoons of Walt Disney Studios. Radio absorbed much of the talent of vaudeville as it began to lose popularity in the 1920s, and this merger signaled the rise of sound film, many of whose earliest stars got their start on the vaudeville stage.