Launch from Cape Canaveral (KSC); landing at Cape Canaveral (KSC); ISS-ULF-5 / ELC-4.

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 launch of space shuttle Discovery had to be srcubbed for several times. Target launch date was November 01, 2010. On November 02, 2010, while readying Discovery for launch, engineers reported an electrical issue on the backup Main Engine Controller (MEC) mounted on Engine No. 3 (SSME-3). On November 05, 2010 Discovery's launch attempt, a hydrogen leak was detected at the Ground Umbilical Carrier Plate (GUCP) during the fueling process. Additional inspection of the tank then revealed cracks in foam insulation in the flange between the intertank and liquid Oxygen tank. The insulation was cut away for additional inspection revealing two additional 9-inch metal cracks on either side of an underlying structural rib called "stringer S-7-2". NASA managers then decided to cut away additional foam and observed two more cracks on a stringer known as S-6-2 adjacent to the two original cracks. They were found on the far left of removed foam on the flange area between the intertank and the liquid Oxygen tank. However these cracks appeared to had suffered less stress than the originally found. Scanning of the stringers on the Liquid Oxygen/Intertank flange was completed on November 23, 2010.

Fueling process on December 17, 2010 saw no problems. But for final tests, NASA directors decided a complete Rollback. The new launch date was set for not earlier than February 03, 2011. On January 06, 2011, NASA managers decided to give engineers additional time to assess external tank cracks and repair scenarios. The launch was delayed for not earlier than February 24, 2011.
On January 15, 2011 Timothy Kopra was injured in a bicycle accident. He was replaced by Stephen Bowen on January 19, 2011.

Following a two day solo flight Discovery docked to the ISS on February 26, 2011. Joint operations with the ISS expedition 26 were performed.
Later this day Michael Barratt and Nicole Stott used the station’s robotic arm to pluck Express Logistic Carrier 4 from the shuttle cargo bay and hand it off to the shuttle’s arm, operated by Alvin Drew and Eric Boe. After moving the base of Canadarm2, the shuttle arm was to hand ELC-4 back for installation on the Earth-facing side of the station’s starboard truss. There it will be used for stowage of spare parts, including a spare radiator launched aboard Discovery.

The first EVA by Stephen Bowen and Alvin Drew occured on February 28, 2011 (6h 34m). They installed a power extension cable between the Unity and Tranquility nodes to provide a contingency power source should it be required. The spacewalkers moved the failed ammonia pump module that was replaced in August 2010 from an attachment bracket to a stowage platform adjacent to the Quest airlock. Alvin Drew and Stephen Bowen installed a piece of hardware that will go under a camera on the truss. The hardware will tilt the camera to provide clearance for a spare part to be installed on a future mission. They next replaced a guide for the rail cart system used for moving cargo along the truss. The guides were removed when the astronauts were performing work on the station's starboard Solar Alpha Rotary Joint, which rotates the solar arrays to track the sun.

On March 01, 2011 Michael Barratt and Nicole Stott inched the 58-foot-long space station robotic arm onto a grapple fixture on the Permanent Multipurpose Module (PMM). The arm will lift the fully-loaded 28,353 pound PMM from space shuttle Discovery's cargo bay and carry it to the Earth-facing port on the Unity node, where it will be permanently attached.

The second and final EVA was performed by Stephen Bowen and Alvin Drew on March 02, 2011 (6h 14m). The astronauts removed thermal insulation from a platform, while Stephen Bowen swaped out an attachment bracket on the Columbus module. Stephen Bowen then installed a camera assembly on the Dextre robot then removed insulation from Dextre's electronics platform. Alvin Drew installed a light on a cargo cart and repaired some dislodged thermal insulation from a valve on the truss then remove other insulation from Tranquility. The final task was to "fill" a special bottle with space for a Japanese education payload. The bottle will be part of a museum exhibit for public viewing.

Meanwhile the mission was extended two days.