In 1927, the last cavalry units left the installation, ending 60 years of cavalry history at Fort Warren. In 1930, President Hoover issued a proclamation changing the name of the post to Fort Francis E. Warren, honoring Wyoming's territorial governor and first state governor. Warren was a U.S. Senator for 37 years. He received the Medal of Honor when he was 19 for heroism during the Civil War.

During World War II, Fort Warren was the training center for up to 20,000 of the Quartermaster Corps. More than 280 wooden buildings were constructed without insulation and interior walls to temporarily house the increased number of troops. In the harsh Wyoming winter, waking up in these barracks often meant shaking snow from one's blanket before heading for the just-as-cold communal showers. A prisoner of war camp was also constructed at that time.

In 1949, 80 years after its founding, the fort became Francis E. Warren Air Force Base. As an Air Force Installation, the base was first used as a training facility. The base joined Strategic Air Command in 1958 and organized the nations first wing dedicated solely to intercontinental ballistic missile operations. Atlas D and E missile sites in eastern Wyoming, western Nebraska, and northern Colorado were placed under the command and control of F.E. Warren. In 1960 and 1961, Atlas E missiles were delivered to prepared sites located in the vicinity of Grover, Briggsdale, Nunn, Greeley, and Fort Collins. Placed horizontally in “coffin” shelters, these missiles of the 549th (later 566th) Strategic Missile Squadron remained on alert status until March 1965.