The endothelium of the brain microvasculature is much tighter than that elsewhere in the body. Although brain endothelium appears to possess the same routes for transendothelial transfer as other endothelia, the rarity of some routes leads to an extremely low overall permeability. Cells associated with brain endothelium, particularly astrocytic glial cells, appear to be involved in induction of the low permeability state. Although relatively unaffected by hypoxia and changes in plasma ion concentration, brain endothelial permeability is increased by stretch and shrinkage of endothelial cells, and by inflammatory mediators. Recent evidence suggests that many mediators of increased transendothelial permeability act by raising intracellular free calcium, and causing a contractile event that pulls apart the tight junctions; this also appears to apply to brain endothelium. Comparison of the brain endothelium with the perineurium of peripheral nerve, part of the blood-nerve barrier, suggests that the modulation of brain endothelial permeability seen in pathological situations may give some physiological advantage.