The roles of anatomical and functional abnormalities of the cerebral venous endothelium in the pathogenesis of human CNS inflammatory diseases such as MS and ADEM often remain unrecognized, underinvestigated, and untreated. Rather than these diseases simply being the result of structural disturbances of veins, together with the combined hemodynamic (low/abnormal flow, pressure/congestion), programmatic (arterial, venous, valvular) and environmental (metabolic, hypoxic) stresses to which venous endothelial cells are exposed may render them particularly susceptible to inflammatory activation, contributing to several neurovascular pathologies. Presently, markers of arterial and venous endothelial specification and the role of each cell type in inflammation are now receiving more attention. A more thorough understanding of such mechanisms based on the developmental, cellular, and molecular mechanisms underlying the hemodynamic disturbances of these conditions will open many new therapeutic targets for debilitating diseases such as Alzheimer’s disease and MS.