Introduction: Similarities between the clinical presentation of individuals living with spinal cord injury (SCI) and astronauts are remarkable, and may be of great interest to clinicians and scientists alike. Objectives: The primary purpose of this review is to outline the manner in which cardiovascular, musculoskeletal, renal, immune and sensory motor systems are affected by microgravity and SCI. Methods: A comprehensive review of the literature was conducted (using PubMed) to evaluate the hallmark symptoms seen after spaceflight and SCI. This literature was then examined critically to determine symptoms common to both populations. Results: Both SCI and prolonged microgravity exposure are associated with marked deteriorations in various physiological functions. Atrophy in muscle and bone, cardiovascular disturbances, and alterations in renal, immune and sensory motor systems are conditions commonly observed not only in individuals with SCI, but also in those who experience prolonged gravity unloading. Conclusion: The preponderance of data indicates that similar physiological changes occur in both SCI and prolonged space flight. These findings have important implications for future research in SCI and prolonged space flight.