The Empire State Building is the fifth tallest building in America.
At one point Alistair Smythe attempted to use the Mega-Slayer to abduct Curt Connors. However, Connors transformed into the Lizard and went into the sewer. Smythe then took Margaret Connors hostage and ordered Spider-Man to bring Connors to the top of the Empire State Building in six hours.
Unable to capture the Lizard, Spider-Man went to the Empire State Building and told Smythe that he could not find Connors. However, Smythe believed that Spider-Man was lying and had the Mega-Slayer attack him.
Later when Spider-Man took Maria Taina Elizando web swinging he took her to the top of the Empire State Building.
The Empire State Building was once taken over by an alien race known as the Phalanx but they were stopped by the X-Men.