It is now more than 50 years since the first human space flight took place. Since then some 500 humans have experienced the weightlessness of space flights, mostly during orbital flights, but a few individuals have travelled to the moon and back. At present time astronauts and cosmonauts live and work at the International Space Station (ISS), and the normal duration of a stay at ISS is six months. The human body readapts to the new environment, and therefore is no longer adapted to the normal gravity when returning to earth. For the cardiovascular system this leads to orthostatic intolerance and impaired exercise capacity during the initial period after landing. These symptoms are observed already after spaceflights of 1- 2 week duration. During the US Space Shuttle program with flight durations up to 16 days some 40 per cent of the astronauts could not finish a 10 min stand test and had to interrupt earlier due to signs of impending vasovagal syncope. Several factors act together to cause orthostatic intolerance: Already after 24 h in space there is a manifest reduction of the plasma volume and a redistribution of interstitial fluid from the legs to the head and neck, the latter causing the classical signs of “chicken legs and puffy face”. A headward redistribution of blood and fluid is perceived by volume-regulating mechanisms as an over-all hypervolemia, which is then corrected by a combination reduced fluid intake and increased fluid output. A condition similar to motion sickness during the first days of microgravity contributes to the reduced fluid intake. After a week or so there is a 2-3 kg reduction of body mass to which the reduction of fluid volume has contributed. Upon return to normal gravity the relative hypovolemia manifests itself with reduced stroke volumes during rest and exercise. There is also a reduced sensitivity of the carotid-cardiac baroreflex, but the impact of that on orthostatic tolerance is likely to be small since there are marked tachycardic responses both to standing and exercise. Indirect evidence points to an inability to defend the arterial blood pressure by vasoconstriction in the lower extremities. The responsible mechanism here is not clear; a hypothetical over-expression of beta-2 receptors in resistance vessels has not been substantiated. Neither is the output of sympathetic nerves impaired since muscle-sympathetic neural activity is increased rather than decreased during and after space flight. The aerobic capacity is reduced by up to 25 per cent after space flight and appears proportional to the reduced stroke volume and plasma volume. Apart from the hypovolemia there are signs of moderate cardiac atrophy with a smaller left ventricular myocardial mass and a somewhat stiffer myocardium. As plasma volume is recovered after a week in normal gravity the aerobic capacity and the exercise stroke volume are recovered. With the perspective of human planetary exploration in the future, much present research work is focusing on how to preserve orthostatic tolerance and exercise capacity after extended periods of microgravity, so that explorers arriving to Mars can manage independently of the ground support they would have had if they landed on Earth. Clearly the present exercise prescription of 1- 2 hours of daily work on a cycle ergometer or on a treadmill helps to prevent an even more marked relative hypovolemia than that described above. However, it has little effect on orthostatic intolerance. Moreover, exercise consumes precious resources such as food and oxygen, so there is a need for more time-effective countermeasures, which at the same time should prevent skeletal muscle atrophy and bone demineralization. Present studies in that area include a combination of strength training and artificial gravity.