Oxygen is frequently administered to patients with suspected stroke. However, the role of oxygen therapy in ischemic stroke remains controversial in light of the failure of three clinical trials of hyperbaric oxygen therapy to show efficacy, and the fear of exacerbating oxygen free radical injury. The previous trials had several shortcomings, perhaps because they were designed on basis of anecdotal case reports and little preclinical data. Most animal studies concerning oxygen therapy in stroke have been conducted over the last 6 years. Emerging data suggests that hyperbaric and even normobaric oxygen therapy can be effective if used appropriately, and raises the tantalizing possibility that hyperoxia can be used to extend the narrow therapeutic time window for stroke thrombolysis. This article reviews the history, rationale, mechanisms of action and adverse effects of hyperoxia, the key results of previous hyperoxia studies, and the potential role of oxygen therapy in contemporary stroke treatment.