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Weightlessness during space flight elicits significant losses in bone density, muscle strength, and cardiorespiratory conditioning. Exercise may be considered the primary countermeasure to these changes, yet to date cycle ergometry, treadmill locomotion, and resistive exercise have not been able to produce post flight values equal to those seen at preflight. Improvements in the effectiveness and efficiency of exercise countermeasures will rely on ground based and flight studies that examine the specific stimulus provided in terms of exercise modes, durations, intensities, and frequencies. Biomechanical evaluations should be conducted to determine how different exercise modes affect specific body regions in terms of bone, muscle and cardiovascular stimulus. Flight studies must be carefully designed around operational concerns. Finally, new exercise countermeasures need to be evaluated to determine if they offer additional capabilities beyond current approaches.