Neuroprotective drugs have so far failed clinical trials, at high cost, and intravenous tissue plasminogen activator (i.v. tPA) remains the only FDA-approved acute stroke therapy. Hyperoxia, acting via multiple direct and indirect mechanisms, may be a powerful neuroprotective strategy to salvage acutely ischemic brain tissue and extend the time window for acute stroke treatment. Of the available oxygen delivery methods, hyperbaric oxygen therapy (HBO) appears to be the most potent, while even normobaric oxygen therapy (NBO) may be effective if started promptly after stroke onset. HBO has so far failed to show efficacy in three clinical trials. The failure of these trials is probably attributable to factors such as delayed time to therapy, inadequate sample size and use of excessive chamber pressures. Previous trials did not assess long-term benefit in patients with tissue reperfusion. In this modern era of stroke thrombolysis and advanced neuroimaging, oxygen therapy may have renewed significance. If applied within the first few hours after stroke onset or in patients with imaging evidence of salvageable brain tissue, oxygen therapy could be used to 'buy time' for the administration of thrombolytic or neuroprotective drugs. This article reviews the history and current rationale for using oxygen therapy in stroke, the mechanisms of action of HBO and the results of animal and human studies of hyperoxia in cerebrovascular diseases.