Orpheum Theater, 126 Second Avenue, ca. 1979.

In 1868, Elizabeth Blackwell established at 126 Second Avenue the Women's Medical College of the New York Infirmary, at the time, the only institution that would train women to be doctors in New York City. The year after the College's establishment, Blackwell left for England, leaving the College under her younger sister Emily's directorship. It remained open until 1899.

After the college closed, the site became the alleged destination of a concert-garden and, in 1904, a theatre. 126 Second Avenue remains one of the oldest continuously operating places of entertainment in Manhattan. Originally called the Players Theatre, it was part of what was then a vibrant Yiddish theatre scene on Second Avenue, also known as the "Jewish Rialto." During the heyday of Yiddish productions, theaters along Second Avenue hosted as many as 20 to 30 shows a night.

In 1958, the theatre became the official home for Off-Broadway productions. It has been the home of the production, Stomp, with over 5,000 performances since its opening night in 1994.