Cerebral edema occurs in many pathologic states and has multiple mechanisms underlying its etiology. Cytotoxic edema refers to increased intracellular fluid volume, whereas vasogenic edema refers to increased interstitial fluid volume. Mechanisms that lead to these processes include impaired axonal transport, microvessel circulatory stasis, impaired ion gradient maintenance, inflammatory factor and free radical-induced blood–brain barrier breakdown, etc. Using the pathophysiology of cerebral edema as a scaffold, a variety of mechanisms can be hypothesized as contributing factors to the development of the structural changes described in Spaceflight Associated Neuro-Ocular Syndrome (SANS). This chapter will explore how the principles of cerebral edema may help explain the etiology of SANS and why the microgravity environment would provide a unique set of factors that would set this syndrome apart from other well-known terrestrial causes of similar structural changes.