The song, written by bassist Dee Dee Ramone, refers to what was then a well-known spot for male prostitution in New York City, known as "the Loop". The area was a center of gay nightlife decades before the West Village became prominent, and was home to well-known hustler bars, most notably Cowboys, Rounds, and Red, from the 1970s through the 1990s.

Shortly after the song was written, the block between 3rd and Lexington avenues was cleared to make way for one of Manhattan's tallest skyscrapers, the Citigroup Center. Years later, the Lipstick Building was built on the east side of 3rd Avenue at 53rd. However, gay hustlers remained in abundance at bars on 53rd between 3rd and 1st avenues.

In the song, Dee Dee's lyrics referenced the wavering feelings of a "straight" teenage hustler who confuses being purchased with being attractive and also confuses violence with masculinity. Legend has it that Dee Dee himself, bassist and primary songwriter of the Ramones, worked as a hustler in order to pay for his heroin habit. He refused to discuss the matter, fueling speculation that the track is, in fact, autobiographical. In the film End of the Century: The Story of the Ramones, other members the band seem to insinuate that the story is indeed true. At the end of the song the protagonist of "53rd and 3rd," who bemoans the fact that he's "the one they never pick," is finally chosen by a customer but produces a razor blade to do "what God forbade." He is chased by the police, but is pleased that he has "proved that [he's] no sissy."

The song also lent its name to an influential British indie pop label. It was run by The Pastels' Stephen Pastel and friends, and released records by the likes of Talulah Gosh, Shop Assistants, The Vaselines, The Soup Dragons, and BMX Bandits.

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