The blood–brain barrier (BBB) is a complex vascular structure consisting of microvascular endothelial cells that line the vessel wall, astrocyte end‐feet, pericytes, as well as the basal lamina. BBB cells act in concert to maintain the characteristic impermeable and low paracellular flux of the brain vascular network, thus ensuring a homeostatic neuronal environment. Alterations in BBB stability that occur during injury have dire consequences on disease progression and it is clear that BBB cell‐specific responses, positive or negative, must make a significant contribution to injury outcome. Reduced oxygenation, or hypoxia, is a characteristic of many brain diseases that significantly increases barrier permeability. Recent data suggest that hypoxia‐inducible factor (HIF‐1), the master regulator of the hypoxic response, probably mediates many hypoxic effects either directly or indirectly via its target genes. This review discusses current knowledge of physiological cell‐specific regulation of barrier function, their responses to hypoxia as well as consequences of hypoxic‐ and HIF‐1‐mediated mechanisms on barrier integrity during select brain diseases. In the final sections, the potential of current advances in targeting HIF‐1 as a therapeutic strategy will be overviewed.