It operates C-17 Globemaster III aircraft carrying out United States Air Force global transport missions, duties which involve airlift and airdrop missions as well as provision of services and support in order to promote quality of life for both soldiers and civilians in situations requiring humanitarian aid.

The squadron moved to Nadzab Airfield, New Guinea in August 1944 to support the Allied effort to push Japanese forces off the island.

The squadron was first moved to Occupied Japan, where it conducted airlift missions in support of Fifth Air Force and MacArthur's headquarters from Atsugi Airfield, near Tokyo.

The 21st flew needed supplies and equipment within the Southwest Pacific area to widely scattered airfields in the Philippines, Okinawa and the bases in the Mariana Islands.

The squadron carried much needed equipment and supplies, along with personnel across the Sea of Japan to marginal dirt airstrips in South Korea on an almost continuous basis.

The squadron participated in all major engagements in Korea, including the massive airdrops at Sunchon in which 290.8 tons of supplies and 1,093 paratroopers were dropped in three days.

As the level of American involvement increased in the ongoing conflict in Southeast Asia, the C-130s of the squadron were becoming a more common sight during the 1960s in support of operations.

In 1968, during the siege of Khe Sanh, crews from the 21st performed massive combat airdrops and assault landing supporting the besieged outpost.

[5] During the 1980s, the 21st frequently participated in exercises including Team Spirit, Foal Eagle, Tandem Orbit, and Cope Thunder.

The 21st, in turn, was transferred to Travis Air Force Base, California[5] where it took over the assets of the Lockheed C-5 Galaxy 75th Airlift Squadron.

The 75th was transferred in turn to Ramstein Air Base, Germany where it took over the Douglas C-9 Nightingale medical Evacuation mission of USAFE.

[5] They were also involved in several humanitarian missions in 1994 including transportation of tons of badly needed medical supplies and food to disease-ravaged Rwanda, missions in support of the Haitian and Cuban relief efforts, and closer to home, the 21st provided the first C-5 crew to fly critically needed firefighters equipment to earthquake-stricken Los Angeles.