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Prolonged spaceflight can induce physiologic and pathologic abnormalities in the central nervous system (CNS). Our knowledge of the adaptive and/or detrimental effects of spaceflight on the structure and function of the nervous system is limited. Substantial effort has been devoted to identifying and developing reliable indicators to characterize and predict CNS injury and dysfunction associated with prolonged exposure to major components of the space environment including microgravity, physiological/psychological stress, and radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) outside of low earth orbit (LEO). The blood-brain barrier (BBB) is a semi-permeable membrane that is essential to maintain homeostasis of the brain microenvironment. Oxidative stress or other environmental stressors may disrupt BBB integrity and increase permeability leading to immune cell infiltration and undesirable neuroinflammation. The focus of this review article is on BBB damage associated with spaceflight and space radiation in rodent and human studies. We will highlight potential biomarkers for this damage, including site-specific and circulating neuroinflammatory factors, BBB structural and brain parenchyma proteins, and neuroimaging tools for BBB damage evaluation. These knowledge will help to understand the risks associated with space travel and are also critical for novel countermeasure development to mitigate the space flight risk to astronaut performances., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)