Krikalev was selected as a Russian cosmonaut in 1985. He is a veteran of six space flights, logging a total of 803 days, 9 hours and 39 minutes in space, including eight EVA's (space walks).

In October 1992, NASA announced that an experienced cosmonaut would fly aboard a future Space Shuttle mission. Krikalev was one of two candidates named by the Russian Space Agency for mission specialist training with the crew of STS-60, the first joint U.S./Russian Space Shuttle Mission.

On February 3, 1994, Krikalev launched aboard STS-60, which was the second flight of the Space Habitation Module-2, and the first flight of the Wake Shield Facility. During the 8-day flight, the crew conducted a wide variety of materials science experiments, both on the Wake Shield Facility and in the Spacelab, earth observation, and life science experiments. Krikalev conducted significant portions of the Remote Manipulator System operations during the flight. Following 130 orbits of the Earth in 3,439,705 miles, STS-60 landed at Kennedy Space Center, Florida, on February 11, 1994.

Krikalev returned to duty in Russia following his American experience on STS-60. However, he periodically returned to the Johnson Space Center in Houston to work with CAPCOM in Mission Control and ground controllers in Russia supporting joint U.S./Russian Missions. To date, he has supported STS-63, STS-71, STS-74 and STS-76.

Krikalev flew on the first International Space Station (ISS) assembly mission, STS-88 Endeavour, from December 4-15, 1998. During the 11-day mission, two crew members performed three EVA’s to connect umbilicals and attach tools/hardware for use in future EVA’s. The crew also performed IMAX Cargo Bay Camera operations, and deployed two satellites, Mighty Sat 1 and SAC-A.

Krikalev was the Commander of Expedition-11, which launched on a Soyuz rocket, from the Baikonur Cosmodrome in Kazakhstan on April 14, 2005, and docked with the ISS on April 16, 2005. During their 6-month stay aboard the station, the crew continued station maintenance, worked with scientific experiments, and performed a spacewalk in Russian spacesuits from the Pirs Airlock. The Expedition-11 crew landed in their Soyuz spacecraft in the steppes of Kazakhstan on October 10, 2005.

Krikalev was awarded the title of Hero of the Soviet Union, the Order of Lenin, the French title of L'Officier de la Légion d'Honneur, and the new title of Hero of Russia. Krikalev was awarded the NASA Space Flight Medal in 1994 and 1998. Krikalev was also a member of the Russian and Soviet national aerobatic flying teams, and was Champion of Moscow in 1983 and Champion of the Soviet Union in 1986.