Discovery carried the Italian-built Multi-Purpose Logistics Module (MPLM) Leonardo, with more than two tons of equipment and supplies aboard. This was the fourth trip to the station for Leonardo. Equipment and supplies no longer needed on the station were moved to Leonardo before it is unberthed on Flight Day 10 and put back into Discovery's cargo bay for return to Earth.

Two 6.5-hour spacewalks are scheduled for Sellers and Fossum on the fifth and seventh days of the mission. The first spacewalk will test the 50-foot robotic arm boom extension as a work platform. They will also begin maintenance of the station’s Mobile Transporter (MT) by safing or replacing a cable cutter unit to allow the station’s mobile robotic system to be translated in support of the second spacewalk.

During the second spacewalk the crew will replace the detached cable on the MT, which was inadvertently cut, and its reel assembly. They will also install a spare part for the station’s thermal control system for future use.

During STS-121, mission managers expect to evaluate the high probability of shuttle consumables supporting an extra day for the mission. If an extra day is available, the crew and flight control team are training for a third spacewalk. The third spacewalk would include tasks to test techniques for inspecting and repairing the Reinforced Carbon-Carbon segments that protect the orbiter’s nose cone and wing leading edges.

Undocking is set for Flight Day 11. Discovery's crew will make final preparations for the return home on Flight Day 12, with landing at the Kennedy Space Center's Shuttle Landing Facility on Flight Day 13.

Bring a third crew member to the station.

The mission did ferry European Space Agency astronaut Thomas Reiter, who remained on the station and worked with the station crew under a contract between ESA and the Russian Federal Space Agency.