On his first flight, STS-27 (December 2-6, 1988), Shepherd served on the crew aboard the Space Shuttle Atlantis. The mission lasted 105 hours and carried Department of Defense payloads.
On STS-41 (October 6-10, 1990), during 66 orbits of the Earth, the crew aboard the Space Shuttle Discovery successfully deployed the Ulysses spacecraft, starting it on a four-year journey (via Jupiter) to investigate the polar regions of the Sun.
Shepherd flew a third mission, STS-52 (October 22 - November 1, 1992), aboard the Space Shuttle Columbia. The 10-day mission deployed the Laser Geodynamic Satellite (LAGEOS), and conducted U.S. microgravity payload experiments.
Manned five crew. Deployed a classified payload. Orbits of Earth: 68. Landed at: Runway 17 dry lake bed at Edwards Air Force Base, . Landing Speed: 359 kph. Touchdown miss distance: 447.00 m. Landing Rollout: 2,171.00 m. Payloads: DoD Mission.
Manned five crew. Deployed Ulysses spacecraft. Payloads: Deploy Ulysses, Shuttle Solar Backscatter Ultraviolet, Intelsat Solar Array Coupon, Solid-Surface Combustion Experiment, Investigations Into Polymer Membrane Processing, Chromo-some and Plant Cell Division in Space, Physiological Systems Experiment, Voice Command System, Radiation Monitoring Equipment III, Air Force Maui Optical Site.
Deployed Lageos 2, CTA. Payloads: Laser Geodynamic Satellite (LAGEOS) II/ Italian Research Interim Stage (IRIS), Canadian Experiments (CANEX) 2, United States Micro-gravity Payload (USMP) 1, Attitude Sensor Pack-age (ASP), Tank Pressure Control Experiment (TPCE), Physiological Systems Experiment (PSE), Heat Pipe Performance (HPP) experiment, Commercial Protein Crystal Growth (CPCG), Shuttle Plume Impingement Experiment (SPIE), Commercial Materials ITA Experiment (CMIX), Crystals by Vapor Transport Experiment (CVTE).
Soyuz 31 delivered the Expedition One crew to the International Space Station with Gidzenko as the Soyuz crew commander with the call-sign 'Uran'. The spacecraft docked at Zvezda's rear port at 0921 GMT on November 2. The hatch to Zvezda was opened at 1023 GMT. Once aboard ISS, Shepherd became the ISS Commander, with 'Station Alpha' as the ISS callsign. Soyuz TM-31, with Shepherd, Gidzenko and Krikalyov aboard, undocked from the -Y port on Zvezda on February 24, 2001 at 1006 GMT and redocked with the -Z port on Zarya at 1037 GMT. This freed the Zvezda port for a Progress resupply ship.