During the STS-121 mission to the International Space Station (ISS), the crew of Space Shuttle Discovery continued to test new equipment and procedures for the inspection and repair of the thermal protection system that is designed to increase the safety of the Space Shuttles. It also delivered more supplies and cargo for future ISS expansion.

After the Columbia accident, NASA decided that two test flights would be required and that activities that were originally assigned to STS-114 would need to be divided into two missions because of the addition of post-Columbia safety tests. Before the accident, Columbia had been assigned to missions STS-118 and STS-121. The STS-118 mission, also an International Space Station flight, was at first reassigned to Discovery, but was later assigned to Space Shuttle Endeavour.

Discovery arrives at the launch pad, for STS-121.
The STS-121 mission was originally to have sent Columbia to service the Hubble Space Telescope. However, that servicing mission was given another designation on the manifest before the disaster and the designation of STS-121 once again became available. Since STS-115 through STS-120 were already delegated to existing missions, NASA selected the lowest available mission designation for the second test flight. Hence, the mission following STS-114 is STS-121.

Launch of STS-121 on 4 July 2006
The STS-121 test flight mission was originally to be flown aboard Atlantis in September 2005, after Space Shuttle Discovery flew STS-114, but a problem with the landing gear of Atlantis moved Discovery ahead to fly STS-121. After the return of Discovery to California following the completion of STS-114, scheduling again changed. Atlantis was moved up to fly the STS-115 mission (whose launch was planned for August 2006) and Discovery was to fly the STS-121 mission as originally planned. The launch of the STS-121 mission was delayed until July 2006 as well, due to an unresolved foam debris and the Engine Cut Off (ECO) sensor issue from STS-114.

On 12 May 2006, Discovery was moved from the Orbiter Processing Facility to the Vehicle Assembly Building, where it was mated to its External Tank and SRBs. Rollout to Pad 39B occurred on 19 May 2006 ahead of the planned launch, during the July 2006 launch window, which existed for about ten minutes each day between 1 and 19 July.