Space flight, as well as ground based models for it, induces reductions in muscle mass, muscle function, bone mass and thus a weakening of the skeleton’s structural strength. The combination of these alterations must be expected to greatly increase the risk of falls and fractures upon re-entry into gravitational fields, with potentially deleterious consequences e.g. on Mars. Therefore, the quest to maintain musculoskeletal health in space has prompted the development of countermeasures, of which many involve physical exercise. Such developments can only be done in a rationale way if the mechanisms that underlie the alterations are understood. With regards to muscle, the space-induced reduction in size is very prominent in the legs, somewhat less in the trunk and absent in the legs. This is mostly understood as disuse atrophy, since astronauts cannot load their leg muscles forcefully whilst in space. Accordingly, bed rest is considered as a valid ground based model of space flight (1), with obvious relevance for clinical medicine. The atrophy is most severe in those muscles that normally act against gravity, and it is also more pronounced in mono-articular muscles than in bi-articular muscles. Finally, it is also important to notice that the loss in muscle strength after space flight is in excess of the loss in anatomical cross section (2). The possible causes are currently under investigation. With regards to bone, its structural weakening in space had initially been ascribed to endocrine disturbances, e.g. a lack of vitamin D. However, it has to be appreciated that bone losses are occurring in the lower, but not in upper extremities. We therefore argue that endocrine and nutritional effects, although important confounders, are unlikely to be the primary cause. It is now generally accepted that bones adapt to mechanical stimuli. The mechanostat theory proposes that bone strains are regulated in the fashion of a negative feed-back loop (3), and that bones can thereby respond to alterations in their loading. Controversy, however, still exists as to where the most important forces arise from. Whilst it is often thought that gravitational bone loading, or even weight bearing itself would constitute the primary osteogenic stimulus, biomechanical analyses suggest that the greatest forces arise from muscle contraction. In order to promote our understanding of the musculature’s role in the maintenance of bone, evidence from three strings of research is accumulated. Firstly, resistive exercise was performed as a countermeasure during bed rest, with the intention to safeguarding bone strength through the maintenance of muscle strength. In the long term bed rest (LTBR) study, resistive flywheel exercise was performed 2-3 times per week during 90 days of bed rest. This exercise regimen was highly efficient for the knee extensor, but not for the plantar flexor muscles, and it failed to achieve a significant benefit for the hip or the tibia (4). In the first Berlin bed rest (BBR) study, however, the combination of resistive exercise with whole body vibration performed 11 times per week was found to be fully efficient for plantar flexor muscle strength and for tibial bone mass (5). The second Berlin bed rest study then established the specific benefit of vibration for bone in the bed rest model. The second line of evidence for the muscle-bone hypothesis derives from a novel model of tibial unloading that has recently been developed in our laboratory. In particular, an orthosis has been designed that replaces the function of the plantar-flexor muscle-tendon complex, but allows a normal gait pattern and therefore will maintain the tibia’s gravitational loading. The third line of evidence, finally, is a study that is currently assessing the temporal and quantitative relationship between muscle contractions and bone strains in humans. Taken together, the available evidence underlines the important role of muscle contractions for the maintenance of bone. Exercise countermeasures for the maintenance of bone in space therefore will probably have to involve forceful muscle contractions.