He was inspired to pursue a career in the field after reading about NASA's Langley Memorial Aeronautical Laboratory in Virginia.

In January 1937 Gilruth was hired at NACA's Langley Memorial Aeronautical Laboratory, where he performed flight research.

Gilruth had been working on hypersonic missile rockets as the assistant director of the Pilotless Aircraft Research Division of NACA.

The dynamic quickly changed after the Soviets succeeded in launching Sputnik, and Gilruth became involved in the transition of NACA into NASA.

[citation needed] In 1961, when President John F. Kennedy announced that America would put a man on the Moon before the end of the decade (the 1960s) and bring him back safely to Earth, Gilruth was "aghast" and unsure that such a goal could be accomplished.

He was integral to the creation of the Gemini program, which he advocated as a means for NASA to learn more about operating in space before attempting a lunar landing.