It is not widely appreciated how deleterious prolonged periods of non–weight-bearing are to skeletal integrity. Rates of decline in humans exposed to prolonged spaceflight, for example, are about 10-fold greater than those observed in postmenopausal women and are associated with a significant loss of bone strength. New data on the efficacy of muscle contraction independent of weight bearing in preventing disuse osteopenia suggest that there may not be an absolute requirement for ground reaction forces to maintain bone mass. Mechanisms for disuse osteopenia are likely to involve a number factors contributing to the integrated physiologic response, including changes in interstitial fluid pressures, input from the sympathetic nervous system, and changes in bone marrow osteoprogenitor cell populations. Exciting new data using hindlimb unloaded rodents are defining the important role of the protein sclerostin in regulating Wnt/β-catenin signaling and subsequent loss of bone during periods of disuse.