His flights include commanding the Apollo 10 mission in May 1969 that orbited the Moon, preparing the way for the Apollo 11 landing that followed two months later. He was also commander of the Apollo–Soyuz Test Project in 1975. Stafford was selected as an astronaut in 1962.

He left NASA in 1975 to assume command of the Air Force Flight Test Center. In 1990 and 1991 Stafford headed a Synthesis Group, organized by NASA and the White House, to recommend future strategy in space exploration.