Exposure to a microgravity environment decreases the maximal rate of O2 uptake (VO(2max)) in healthy individuals returning to a gravitational environment. The magnitude of this decrease in VO(2max) is, in part, dependent on the duration of microgravity exposure, such that long exposure may result in up to a 38% decrease in VO(2max). This review identifies the components within the O(2) transport pathway that determine the decrease in postmicrogravity VO(2max) and highlights the potential contributing physiological mechanisms. A retrospective analysis revealed that the decline in VO(2max) is initially mediated by a decrease in convective and diffusive O(2) transport that occurs as the duration of microgravity exposure is extended. Mechanistically, the attenuation of O(2) transport is the combined result of a deconditioning across multiple organ systems including decreases in total blood volume, red blood cell mass, cardiac function and mass, vascular function, skeletal muscle mass, and, potentially, capillary hemodynamics, which become evident during exercise upon re-exposure to the head-to-foot gravitational forces of upright posture on Earth. In summary, VO(2max) is determined by the integration of central and peripheral O(2) transport mechanisms, which, if not maintained during microgravity, will have a substantial long-term detrimental impact on space mission performance and astronaut health.