A YO-YO system designed for the International Space Station (ISS) underlines the effectiveness of exercises that offer muscle development whilst also maximising muscle effort and the lower part of the body. Quadriceps, buttocks and lower back muscles are heavily involved, and femoral bone, tibial and pelvic and spine area are under considerable mechanical stress. A NASA study entitled “Prescription Development of exercises and equipment for Space Travel” by Dr. Gary Dudley and colleagues at the Kennedy Space Center, highlighted the use of functional magnetic resonance imaging (MRI) to justify the use of the YO-YO systems in the absence of gravity. Further experiments conducted with NASA and the European Space Agency in relation to a 17-day mission in the spacecraft Space Shuttle Columbia (STS-78) have assessed the impact of orbital flight on skeletal muscle. Extensor muscle of the knee was decreased by 8%, the concentric and eccentric force had suffered considerable loss of values. Subsequently, a YO-YO exercise device modified to meet the specific requirements for zero-gravity was launched in one of the Space Shuttle Atlantis’ last missions to the ISS. The YO-YO exercise device allowed the astronauts to develop a good training system and assisted in the regeneration of the affected muscles. The overall benefits and results were much better than expected.