The brain requires glucose and oxygen to maintain neuronal metabolism and function. Cerebral ischemia causes heterogeneous changes in tissue oxygenation and cellular metabolism, with a region of decreased blood flow, the penumbra, surrounding a severely damaged ischemic core. Because oxygenation is central in ischemic neuronal death, it is critical to understand exactly what actual changes occur in interstitial oxygen tension (pO2) in ischemic regions during stroke, particularly the penumbra and ischemic core. Cerebral ischemia induces a complex series of molecular pathways involving signaling mechanisms, gene transcription, and protein formation. Free radicals and oxidative stress have been suggested to be involved in each of the steps in the injury cascade. The goal of this review paper is to summarize the current literature concerning our understanding about cerebral tissue oxygenation changes after cerebral ischemia and reperfusion, the subsequent cellular and physiological changes in response to alteration in tissue oxygenation, and treatment strategies utilized to minimize the detrimental effects caused by stroke.