Prolonged exposure to microgravity poses myriad physiological challenges to the musculoskeletal health of astronauts. During a typical 6-month mission on the International Space Station, astronauts may lose as much as 20% of their muscle mass and 5% of their bone mineral density. Exercise countermeasure systems therefore play a key role in mitigating the deleterious effects of microgravity on human physiology. During the ISS era, exercise countermeasure equipment and protocols have evolved from basic exercise tools and exercise regimes to sophisticated systems and highly personalized workouts that have become ever more effective at combating the effects of muscle atrophy and bone loss. Exercise countermeasure systems have also become more compact, more versatile, and more dependable, which are important characteristics when considering future missions beyond Earth orbit. The suite of exercise countermeasure systems on board the ISS comprises a varied array of exercise platforms, including treadmills, resistance exercise devices, ergometers, and aerobic exercise systems. Each system has been designed to be as effective as possible in maintaining cardiovascular health, bone density, muscle strength, and general overall physical fitness of ISS astronauts. The complement of ISS exercise countermeasure systems has evolved over the years to take advantage of and integrate the latest technological developments such as virtual reality and artificial intelligence with the purpose of not only enhancing astronaut engagement and performance but also improving monitoring of the myriad fitness metrics. Since the ISS serves as a platform for research and development in preparation for extended multiyear missions beyond Earth orbit to Mars, it becomes increasingly important to maximize the efficacy of personalized exercise prescriptions that are not only targeted to specific astronaut requirements but also to specific factors such as age, gender, fitness level, and mission duration. Furthermore, given the confines of the Orion spacecraft and Service Module, life support engineers face the challenge of downsizing the current ISS countermeasures while still preserving astronaut health and fitness.