Abstract Background The harsh environmental conditions during space travel, particularly weightlessness, impose a major burden on the human body including the cardiovascular system. Given its importance in adjusting the cardiovascular system to environmental challenges, the autonomic nervous system has been in the focus of scientists and clinicians involved in human space flight. This review provides an overview on human autonomic research under real and simulated space conditions with a focus on orthostatic intolerance. Methods The authors conducted a targeted literature search using Pubmed. Results Overall, 120 articles were identified and included in the review. Conclusions Postflight orthostatic intolerance is commonly observed in astronauts and could pose major risks when landing on another celestial body. The phenomenon likely results from changes in volume status and adaptation of the autonomic nervous system to weightlessness. Over the years, various non-pharmacological and pharmacological countermeasures have been investigated. In addition to enabling safe human space flight, this research may have implications for patients with disorders affecting cardiovascular autonomic control on Earth.