Abstract: A variety of physiological changes are experienced by astronauts during both short- and long-duration space missions. These include space motion sickness, spatial disorientation, orthostatic hypotension, muscle atrophy, bone demineralization, increased cancer risk, and a compromised immune system. This review focuses on countermeasures used to moderate these changes, particularly exercise devices that have been used by National Aeronautics and Space Administration astronauts over the past six decades as countermeasures to muscle atrophy and bone loss. The use of these devices clearly has shown that a microgravity environment places unusual demands on both the equipment and the human users. While it is of paramount importance to overcome microgravity-induced musculoskeletal deconditioning, it also is imperative that the exercise system (i) is small and lightweight, (ii) does not require an external power source, (iii) produces 1g-like benefits to both bones and muscles, (iv) requires relatively short durations of exercise, and (v) does not affect the surrounding structure or environment negatively through noise and/or induced vibrations.