The importance of the blood-brain barrier (BBB) in maintaining brain homeostasis cannot be better appreciated than during disease states, where disruption of its function is associated with dramatic detrimental clinical outcome. For decades, neuroscientists and neurobiologists investigated most neurological diseases under the prism of a neuro-centric view, considering the contribution of non-neural components of the CNS (BBB, choroid plexus) negligible or even irrelevant. However, recent reviews have highlighted the importance of BBB breakdown in major neurological diseases. Hypoxia, as well as hypoxia/reoxygenation, are key components of many neurological diseases and have been shown to contribute to barrier disturbance and dysfunction significantly. Since the master regulator of the hypoxic response, hypoxia inducible factor 1 (HIF-1), is a key determinant for adaptation of cells and tissues to oxygen deprivation, it is likely that this transcription factor also plays a key role in barrier permeability. The possible future use of HIF-1 stabilizers for treatment of diseases characterized by oxygen deprivation to increase neuronal/cell survival means this question is now very pertinent. This review will focus its attention on the role of HIF-1 in BBB breakdown following hypoxic/ischemic injury and the implications for such therapies in a clinical setting.