Muscle and bone form as a result of life in a 1-g environment and the mechanical forces exerted on the body. In microgravity, support muscles such as those in the calf and thigh decline in volume, strength, and mass. Similarly, bones lose calcium, the mineral from which they derive their structure and strength, through the process of demineralization. Is the reported loss of muscle and bone mass that occurs during spaceflight self-limiting or does it continue? Is it permanent or is it reversible? Could the parallel loss of muscular strength and coordination jeopardize the return of piloted spacecraft or limit work capability and performance for surface operations on Mars? This chapter examines the effects of spaceflight on structure and function of the musculoskeletal system, what the implications of such changes might be for long-duration exploratory missions, and what countermeasures might be employed to prevent undesirable changes (Fig. 5.1).