Oxygen is one of the most commonly used therapeutic agents. Injudicious use of oxygen at high partial pressures (hyperoxia) for unproven indications, its known toxic potential, and the acknowledged roles of reactive oxygen species in tissue injury led to skepticism regarding its use. A large body of data indicates that hyperoxia exerts an extensive profile of physiologic and pharmacologic effects that improve tissue oxygenation, exert anti-inflammatory and antibacterial effects, and augment tissue repair mechanisms. These data set the rationale for the use of hyperoxia in a list of clinical conditions characterized by tissue hypoxia, infection, and consequential impaired tissue repair. Data on regional hemodynamic effects of hyperoxia and recent compelling evidence on its anti-inflammatory actions incited a surge of interest in the potential therapeutic effects of hyperoxia in myocardial revascularization and protection, in traumatic and nontraumatic ischemicanoxic brain insults, and in prevention of surgical site infections and in alleviation of septic and nonseptic local and systemic inflammatory responses. Although the margin of safety between effective and potentially toxic doses of oxygen is relatively narrow, the ability to carefully control its dose, meticulous adherence to currently accepted therapeutic protocols, and individually tailored treatment regimens make it a cost-effective safe drug.