Wheelock launched to the International Space Station on June 15, 2010, aboard the Soyuz TMA-19 spacecraft with Fyodor Yurchikhin and Shannon Walker.
Wheelock joined the Expedition 24 crew in progress. During the mission he participated in several scientific investigations. On July 31, 2010 a pump module on the exterior of the Space Station failed. Wheelock and Tracy Caldwell-Dyson made three spacewalks to replace the module, during which he sustained long-term damage to his vision. The failed pump module was later returned home on STS-135.
On September 22, 2010, Wheelock took command of the International Space Station at the beginning of Expedition 25. He is the first U.S. Army officer to command the ISS. Wheelock and his crew continued science and maintenance of the space station. Wheelock is sharing pictures of the Earth, station and views of space via Twitter, as Soichi Noguchi did before him. In September 2010, Wheelock tweeted photos from space of Hurricane Earl. He also participated in a NASA Tweetup on March 16, 2011.
He returned to Earth on November 26, 2010 aboard the Soyuz.