When applied individually, exercise countermeasures employed to date do not fully protect the cardiovascular and musculoskeletal systems during prolonged spaceflight. Recent ground-based research suggests that it is necessary to perform exercise countermeasures within some form of artificial gravity to prevent microgravity deconditioning. In this regard, it is important to provide normal foot-ward loading and intravascular hydrostatic-pressure gradients to maintain musculoskeletal and cardiovascular function. Aerobic exercise within a centrifuge restores cardiovascular function, while aerobic exercise within lower body negative pressure restores cardiovascular function and helps protect the musculoskeletal system. Resistive exercise with vibration stimulation may increase the effectiveness of resistive exercise by preserving muscle function, allowing lower intensity exercises, and possibly reducing risk of loss of vision during prolonged spaceflight. Inexpensive methods to induce artificial gravity alone (to counteract head-ward fluid shifts) and exercise during artificial gravity (for example, by short-arm centrifuge or exercise within lower body negative pressure) should be developed further and evaluated as multi-system countermeasures.