The absence of hydrostatic forces, which results in body fluid shifts, and the absence of deformation forces on normally load-bearing tissues, appear to cause the principal disturbances found during and after space flight in the cardiovascular, fluid and electrolyte, erythropoietic, musculoskeletal, and metabolic systems. These alterations produce reduced body fluid volume, reduced musculoskeletal mass, and alterations in basal metabolism, resulting in the following consistent findings of space flight: weight loss, altered body composition, decreased orthostatic tolerance, and a compromised ability to deal with physical activity after returning from a space-flight environment. Specific changes include alterations in hydration status, resulting in a relative dehydration, loss of body calcium stores with a concomitant increase in urinary hydroxyproline, skeletal muscular atrophy, and a negative energy balance after prolonged space flight. Numerous endocrine changes have been determined during space flight, but more sensitive assay developed recently will allow careful determination of other hormone levels, and measurement of some of the primary changes that occur during the first hours of space flight. These results will be integrated into a working systems model of the physiologic response to weightlessness.