INTRODUCTION: During spaceflight missions, astronauts work in an extreme environment with several hazards to physical health and performance. Exposure to microgravity results in remarkable deconditioning of several physiological systems, leading to impaired physical condition and human performance, posing a major risk to overall mission success and crew safety. Physical exercise is the cornerstone of strategies to mitigate physical deconditioning during spaceflight. Decades of research have enabled development of more optimal exercise strategies and equipment onboard the International Space Station. However, the effects of microgravity cannot be completely ameliorated with current exercise countermeasures. Moreover, future spaceflight missions deeper into space require a new generation of spacecraft, which will place yet more constraints on the use of exercise by limiting the amount, size, and weight of exercise equipment and the time available for exercise. Space agencies are exploring ways to optimize exercise countermeasures for spaceflight, specifically exercise strategies that are more efficient, require less equipment, and are less time-consuming. Blood flow restriction exercise is a low intensity exercise strategy that requires minimal equipment and can elicit positive training benefits across multiple physiological systems. This method of exercise training has potential as a strategy to optimize exercise countermeasures during spaceflight and reconditioning in terrestrial and partial gravity environments. The possible applications of blood flow restriction exercise during spaceflight are discussed herein.Hughes L, Hackney KJ, Patterson SD. Optimization of exercise countermeasures to spaceflight using blood flow restriction. Aerosp Med Hum Perform. 2021; 93(1):32–45.