Rest in bed and immersion in water have been used for centuries by physicians and healers in treating injury and disease. The qualitative similarity of acute and chronic responses to bed rest, immersion, and weightlessness has sparked renewed interest in and a resultant greater understanding of the mechanisms of disuse deconditioning. Some combination of changes in hydrostatic pressure, reduced total metabolism (exercise), compression force on weight-bearing bones, as well as psychological factors associated with prolonged confinement in a new environment probably comprise the major input stimuli for the adaptive responses. Virtually every physiological system is affected. Early responses involve the fluid, electrolyte, and blood pressure control systems with significant muscular atrophy and decreases in bone density occurring over weeks and months. Much effort has been expended to describe the various responses to bed rest and immersion with understandably less effort devoted to research during weightlessness. Future research should be directed mainly toward an understanding of the mechanisms of these adaptive responses. Additional work is especially needed to elucidate the effects of deconditioning on drug metabolism, functioning of the immune system, carbohydrate metabolism, protein and peptide metabolism in muscle, and calcium metabolism as it affects integrity of bone.