Kaleri has most recently been in space in 2010 and 2011 aboard the ISS serving as a flight engineer for the long duration Expedition 25/26 missions.

Kaleri took a training course for a spaceflight aboard the Mir orbital station as a backup crew flight engineer of the Mir-3 mission from 1 April to 9 December 1987.

In 2003, he first flew to the International Space Station (ISS) with NASA astronaut Michael Foale on his fourth spaceflight.

The Soyuz TMA-3 spacecraft carrying Kaleri, Foale and ESA astronaut André Kuipers successfully landed in Kazakhstan at 00:11 GMT on 30 April 2004.

Kaleri was a member (Flight Engineer) of the ISS Expedition 25/26, that was launched on 7 October 2010 from Baikonur Cosmodrome, aboard Soyuz TMA-01M spacecraft, together with cosmonaut Oleg Skripochka and NASA astronaut Scott Kelly.

During their mission, Kaleri and the rest of the Expedition 25/26 crew participated in a wide array of research, including fundamental physics, biometric experiments and investigations of crystal growth in space, as well as education outreach.

The main purpose was to complete connections of the cooperative solar array to provide more electrical power to the Mir station.

The two spacewalkers also tested a glue which would have been useful to seal tiny cracks, and applied the new airtight sealant to a special panel imitating a damaged section in Mir's skin.

On 26 February 2004, Kaleri and NASA astronaut Michael Foale floated outside the ISS from the Pirs Docking Compartment airlock.

Although the spacewalk was originally planned for 5 hours and 30 minutes, it was cut short due to a cooling system malfunction in Kaleri's spacesuit.