As a direct consequence of exposure to microgravity, astronauts experience a set of physiological changes which can have serious medical implications when they return to earth. Most immediate and significant are the headward shift of body fluids and the removal of gravitational loading from bone and muscles, which lead to progressive changes in the cardiovascular and musculoskeletal systems. Cardiovascular adaptations result in an increased incidence of orthostatic intolerance (fainting) following flight, decreased cardiac output, and reduced capacity for exercise. Changes in the musculoskeletal system contribute significantly to impaired function experienced in the post-flight period. The underlying factor producing these changes is the absence of gravity, and countermeasures are therefore designed primarily to simulate earthlike movements, stresses, and system interactions. Exercise is one approach that has had wide operational use and acceptance in both the US and Russian space programmes, and it has enabled humans to stay relatively healthy in space for well over a year. Although it remains the most effective countermeasure currently available, significant physiological degradation still occurs. The development of other countermeasures will be necessary for missions of longer duration, for example for human exploration of Mars.