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Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. The cornerstone of neurocritical care management is optimization and maintenance of cerebral blood flow (CBF) and oxygen and substrate delivery to prevent or attenuate this secondary damage. New techniques for monitoring brain tissue oxygen tension (PtiO2) are now available. Brain PtiO2 reflects both oxygen delivery and consumption. Brain hypoxia (low brain PtiO2) has been associated with poor outcomes in patients with brain injury. Strategies to improve brain PtiO2 have focused mainly on increasing oxygen delivery either by increasing CBF or by increasing arterial oxygen content. The results of nonrandomized studies comparing brain PtiO2-guided therapy with intracranial pressure/cerebral perfusion pressure-guided therapy, while promising, have been mixed. More studies are needed including prospective, randomized controlled trials to assess the true value of this approach. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care.