Prolonged bed rest produces profound changes in muscle and bone, particularly of the lower limb. This review first addresses the various models used by researchers to study disuse-induced changes in muscle and bone as observed during prolonged bed rest in humans. Dramatic change in muscle mass occurs within 4-6 wk of bed rest, accompanied by decreases of 6 to 40% in muscle strength. Immobilization studies in humans suggest that most of this lost muscle mass and strength can be regained with appropriate resistance training within several weeks after a period of disuse. Significant decrements in bone mineral density of the lumbar spine, femoral neck, and calcaneus observed in able-bodied men after bed rest are not fully reversed after 6 months of normal weightbearing activity. Importantly, the lost bone mass is not regained for some weeks or months after muscle mass and strength have returned to normal, further contributing to the risk of fracture. Those who enter a period of bed rest with subnormal muscle and bone mass, especially the elderly, are likely to incur additional risk of injury upon reambulation. Practical implications for exercise professionals working with individuals confined to bed rest are discussed.