NASA announced the STS-133 crew on 18 September 2009, and training began in October 2009. The original crew consisted of commander Steven Lindsey, pilot Eric Boe, and mission specialists Nicole Stott Alvin Drew, Michael Barratt, and Tmothy Kopra. However, on 19 January 2011, about a month before launch, it was announced that Stephen Bowen would replace original crew member Tim Kopra, after Kopra was injured in a bicycle accident. All six crew members had experienced at least one spaceflight before; five of the crew members, all but commander Steven Lindsey, were part of NASA's Stronaut Group 18, all being selected in the year 2000.

The mission commander, Steven Lindsey, handed over his position as Chief Of The Astronaut Office position to Peggy Whitson in order to lead the mission. For the first time, two mission crew members were in space when a crew assignment announcement was made, as Nicole Stott and Michael Barratt were aboard the ISS as part of the Expedition 20 crew. During STS-133, Alvin Drew became the last African-American astronaut to fly on the space shuttle, as no African-Americans were among the crews of STS-134 and STS-135. Having flown onboard Atlantis STS-132 mission, Bowen became the first NASA astronaut to be launched on two consecutive missions.

STS-133 (ISS assembly flight ULF5) was the 133rd mission in NASA's Space Shuttle Programme; during the mission, Space Shuttle Discovery docked with the International Space Station. It was Discovery's 39th and final mission. The mission launched on 24 February 2011, and landed on 9 March 2011. The crew consisted of six American astronauts, all of whom had been on prior spaceflights, headed by Commander Steven Lindsey. The crew joined the long-duration six person crew of Expedition 26, who were already aboard the space station. About a month before lift-off, one of the original crew members, Tm Kopra, was injured in a bicycle accident. He was replaced by Sephen Bowen.

The mission transported several items to the space station, including the Permanent Multipurpose Module Leonardo, which was left permanently docked to one of the station's ports. The shuttle also carried the third of four ExPress Logistics Carriers to the ISS, as well as a humanoid robot called Robonaut The mission marked both the 133rd flight of the Space Shuttle program and the 39th and final flight of Discovery with the orbiter completing a cumulative total of a whole year (365 days) in space.

The mission was affected by a series of delays due to technical problems with the external tank and, to a lesser extent, the payload. The launch, initially scheduled for September 2010, was pushed back to October, then to November, then finally to February 2011.