Francis Emroy Warren AFB has the distinction of being the oldest military facility in the Air Force, having begun as a frontier fort of the US Army, originally Fort D. A. Russell. In 1930 the Fort was renamed Fort Francis E. Warren, and again renamed as Warren Air Force Base in 1949. Francis E. Warren was a Medal of Honor recipient in the American Civil War, territorial governor and later first state governor of Wyoming, and first and a very long serving US Senator for Wyoming. The fort and later AFB are named with Senator Warren's full name to avoid confusion with two historical army forts.

Warren had a long and distinguished history as Fort Russell, which served as a post for many well known Americans, including General John "Black Jack" Pershing, "Father of the Air Force" General Billy Mitchell, General Mark Clark, General Benjamin O. Davis, Jr., Dr. Walter Reed, later singer Sammy Davis, Jr., and as a childhood post for the families of singers Neil Diamond and Chris LeDoux. The dirt airstrip at Fort Warren was little used, although it was the site of a famous crash by World War One ace Captain Eddie Rickenbacker, who survived and lived for many years.

Unlike most Army bases now in Air Force service, Fort FE Warren has little Army Air Force service in World War II. In 1947, in a period when most Army Air Bases and Airfields were being inactivated, Fort Warren actually gained a new Army Air Force Command, Air Training Command, with a technical training mission for powermen and radio mechanics. The Fort was soon renamed Francis E. Warren Air Force Base with the creation of the independent Air Force. Through the start of the Cold War and the entire Korean War FE Warren in-processed thousands of technical trainees for service. Interestingly, FE Warren never had, and still does not have, any notable runway and is not suitable for any modern jet planes.

In the late 1950s budgetary restrictions and new developments in weapon technology led to the transfer of the ATC Headquarters out of FE Warren, and conversion of the base to a strategic missile center under Strategic Air Command. In short order FE Warren became the first fully operational ICBM Air Force Base. The first missiles at Warren were various Atlas SM-65 models, from 1960 to 1965, under the newly activated 90th Strategic Missile Wing. These early launch sites were commonly "coffin" launchers, with the missiles stored sideways in shallow underground bunkers, and erected for launch. In the mid-1960s advancements in missile technology led to the Atlas missiles being replaced by 200 of the new Minuteman I missiles, spread over an 8,000 square mile area. Over the later 1960s the Minuteman missiles were transferred to silo launchers. In the early 1970s the silos were hardened for nuclear strike survival, and converted to Minuteman IIIs. Ongoing developments in technology led to installation of the Peacekeeper missiles in the 1980s and another round of super-hardening was performed.

The end of the Cold War reduced the demand for ICBM readiness, and the Peacekeeper missiles were gradually phased out of service from 2002 to 2005. FE Warren's command was transferred to Air Combat Command, then to Air Force Space Command, and recently to the Air Force Global Strike Command. After several unit name changes the 90th has recently been renamed the 90th Missile Wing and is now mainly armed with modernized Minuteman III missiles. Although the strategic need for overwhelming ICBM missile arms has reduced in the last 20 years, the need remains, and FE Warren remains one of the keystone bases in US global strike forces.