Wetherbee was selected as an astronaut candidate in 1984, and became an astronaut in June 1985. He piloted mission STS-32 in 1990 and commanded missions STS-52 (1992), STS-63 (1995), STS-86 (1997), STS-102 (2001), and STS-113 (2002). The final three missions were dockings with Mir and the International Space Station; STS-113 was the last Space Shuttle mission before the "Columbia" disaster.