<p>The National Aeronautics and Space Administration (NASA) in the United States has been studying a fascinating and unique constellation of neuro-ophthalmic findings collectively known as Spaceflight Associated Neuro-Ocular Syndrome (SANS). SANS is unique to the space environment of microgravity and produces novel physiological and pathological findings that have no direct terrestrial equivalent. The neuro-ophthalmic phenomenon is a major physiologic barrier to future planetary spaceflight. The underlying pathophysiology of SANS remains ill-defined, but since its initial report in 2011, several hypotheses have been proposed including increased intracranial pressure, cerebral venous congestion and glymphatic stasis, compartmentalization of CSF within the orbital nerve sheath sub-arachnoid space (SAS), upward brain shift, inflammation, disrupted axoplasmic transport, and radiation exposure. These aetiologies may not be mutually exclusive and may be interconnected, leading to an integrative, multifactorial aetiology of SANS. This paper critically analyses the various hypotheses of this neuro-ophthalmic phenomenon and the connections between the physiologic and anatomical evidence-based changes observed in spaceflight and terrestrial analogues. Continued prospective, longitudinal study and development of practical countermeasures for SANS will be necessary for future human spaceflight missions including the mission to Mars.</p>