Spaceflight and exposure to microgravity have wide-ranging effects on many systems of the human body. At the European Space Agency (ESA), a physiotherapist plays a key role in the multidisciplinary ESA team responsible for astronaut health, with a focus on the neuro-musculoskeletal system. In conjunction with a sports scientist, the physiotherapist prepares the astronaut for spaceflight, monitors their exercise performance whilst on the International Space Station (ISS), and reconditions the astronaut when they return to Earth. This clinical commentary outlines the physiotherapy programme, which was developed over nine long-duration missions. Principles of physiotherapy assessment, clinical reasoning, treatment programme design (tailored to the individual) and progression of the programme are outlined. Implications for rehabilitation of terrestrial populations are discussed. Evaluation of the reconditioning programme has begun and challenges anticipated after longer missions, e.g. to Mars, are considered.