Exposure to microgravity leads to a number of physiological changes, which may cause serious medical implications when returning to Earth. Six degrees head-down tilt bed rest (HDBR) is used to simulate the effects of microgravity on Earth. Postural changes alter the gravitational component of hydrostatic pressure, leading to large changes in the distribution of blood volume. The most immediate effect of microgravity and HDBR is the head-ward shift of body fluids, and returning to Earth has the opposite effects resulting in an increased incidence of orthostatic intolerance (fainting) after long-term exposure to bed rest or space flight. Cardiovascular adaptations result in decreased cardiac output and reduced exercise capacity. Cardiac atrophy and hypovolemia are likely to contribute independently to orthostatic intolerance after bed rest. Additionally, removal of gravitational loading from bone and muscles leads to progressive changes in the musculoskeletal systems contributing significantly to the impaired functions experienced in the post-flight period. Physical exercise is the most effective countermeasure currently available and has received operational use and acceptance in space and during prolonged bed rest. Daily supine cycle exercise prevents cardiac atrophy and can prevent post HDBR orthostatic intolerance only when combined with plasma volume restoration.