In anticipation of post-Apollo projects such as the Space Shuttle program, it was renamed the Vehicle Assembly Building on February 3, 1965.

Initially, during the planning of Kennedy Space Center, as many as five launch pads were proposed, and designs for a six-bay VAB were drawn up.

Bay 2, located on the west side of the building (farther from the launch pads), saw limited use during the Saturn V era and was eventually converted into a storage area for the Shuttle program.

Before the destruction of Space Shuttle Columbia in 2003, NASA installed a sub-roof inside the VAB to deal with falling concrete debris due to the building's age.

The north end of the Vehicle Assembly Building (VAB) contains four “high bays” designed as enclosed, protected spaces for stacking rocket stages, payloads, and other components vertically on a mobile launcher platform.

Components and stages typically enter the VAB through the south side, which houses eight "low bays" used for storage and pre-assembly preparations.

[3] When the building's large doors are opened, fog can enter and linger, leading to incorrect but persistent rumors that the VAB generates its own weather or forms clouds.

[16] The American flag painted on the building was the largest in the world when added in 1976 as part of United States Bicentennial celebrations, along with the star logo of the anniversary, later replaced by the NASA insignia in 1998.

[18] The most extensive exterior damage occurred during the storm season of 2004, when Hurricane Frances blew off 850 14-by-6-foot (4.3 m × 1.8 m) aluminum panels from the building, resulting in about 40,000 square feet (3,700 m2) of new openings in the sides.

Some of these panels are "punch-outs", designed to detach from the VAB when a large pressure differential is created on the outside vs. the inside.

[15] The VAB could be used to some extent for assembly and processing of any future vehicles using Launch Complex 39, in addition to renovations for SLS capabilities.

On June 16, 2015, NASA released an announcement for proposals (AFP) seeking interest in using the VAB High Bay 2 and other complex facilities for commercial use in "assembling, integration, and testing of launch vehicles".

[21] On April 21, 2016, NASA announced the selection of Orbital ATK (bought by Northrop Grumman as of 2019) to begin negotiations for High Bay 2.

[22] NASA subsequently completed the agreement in August 2019 to lease High Bay 2 and Mobile Launcher Platform 3 to Northrop Grumman for use with their OmegA launch vehicle.