The street has several major landmarks, including (from east to west) the headquarters of the United Nations, the Chrysler Building, Grand Central Terminal, the New York Public Library Main Branch, Times Square, and the Port Authority Bus Terminal.

[5] Cornelius Vanderbilt began the construction of Grand Central Depot in 1869 on 42nd Street at Fourth Avenue as the terminal for his Central, Hudson, Harlem and New Haven commuter rail lines, because city regulations required that trains be pulled by horse below 42nd Street.

It was only after the beginning of the 20th century that the street saw entertainment venues being developed around Times Square and upscale office space around Grand Central Terminal.

[9] In the first two decades of the 20th century, eleven venues for legitimate theatre were built within one block of West 42nd Street between Seventh and Eighth Avenues.

[12] By the 1920s, The New York Times reported that several high-rise developments were "radically changing the old-time conditions" along East 42nd Street,[13] including the Chanin, Lincoln, Chrysler, and Daily News Buildings, as well as Tudor City.

[14] The block of 42nd Street between Second and First Avenues was originally only 40 feet (12 m) wide, passing through a steep bluff known as Prospect Hill.

[16][21] The board provisionally authorized the street widening in June 1949, and Manhattan's borough president announced in December 1949 that work would commence shortly.

[9] Lloyd Bacon and Busby Berkeley's 1933 film musical 42nd Street, starring 30s heartthrobs Dick Powell and Ruby Keeler, displays the bawdy and colorful mixture of Broadway denizens and lowlifes in Manhattan during the Depression.

The book Sleazoid Express, a travelogue of the 42nd Street grindhouses and the films they showed, describes the unique blend of people who made up the theater-goers: depressives hiding from jobs, sexual obsessives, inner-city people seeking cheap diversions, teenagers skipping school, adventurous couples on dates, couples-chasers peeking on them, people getting high, homeless people sleeping, pickpockets...[25]While the street outside the theatres was populated with: phony drug salesman ... low-level drug dealers, chain snatchers ... [j]unkies alone in their heroin/cocaine dreamworld ... predatory chickenhawks spying on underage trade looking for pickups ... male prostitutes of all ages ... [t]ranssexuals, hustlers, and closety gays with a fetishistic homo- or heterosexual itch to scratch ...

[25] For much of the mid and late 20th century, the area of 42nd Street near Times Square was home to activities often considered unsavory,[26] including peep shows.

[28] By the 1960s, East 42nd Street between Park and Second Avenues contained more headquarters of industries than any other place in the United States except Chicago or Pittsburgh.

[32] In 2025, the New York City Department of Transportation announced that the block of 42nd Street between Seventh and Eighth Avenues would be upgraded to protect it from terrorist attacks.

The project, budgeted at $57 million, would include adding steel bollards, installing sewage pipes, and widening the sidewalks and bus lanes.