Prolonged microgravity exposures induce physiological changes that result in deconditioning of the cardiovascular, neurosensory, and musculoskeletal systems. These changes may have important implications as flight durations lengthen and specific mission tasks place higher demands on crewmembers (e.g., space station construction, extravehicular activity contingencies, emergency egress). Historically, the United States and Russia have incorporated a variety of countermeasures in an effort to maintain human health and performance of crewmembers before, during, and after space flight. The NASA countermeasure strategy is focused on the validation of exercise prescriptions and systems for a variety of flight programs: Space Shuttle, Mir, and International Space Station (ISS). The development and implementation of exercise countermeasure prescriptions and modalities require: 1) an understanding of the performance requirements for specific occupational activities and physiological alterations resulting from space flight; 2) hardware integration based on resource allocation of the specific flight program/vehicle and; 3) the ability to customize protocols for each crewmember based on individual mission assignments, baseline fitness status, and available provisions (e.g., time, training, and hardware). This consolidated strategy is designed to provide a comprehensive exercise countermeasure system for optimizing human performance and assuring crew safety as space travel evolves into the next century.