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Oxygen therapy is an integral part of the treatment of critically ill patients. Maintenance of adequate oxygen delivery to vital organs often requires the administration of supplemental oxygen, sometimes at high concentrations. Although oxygen therapy is lifesaving, it may be associated with deleterious effects when administered for prolonged periods at high concentrations. Here, we review the recent advances in our understanding of the molecular responses to hypoxia and high levels of oxygen and review the current guidelines for oxygen therapy in critically ill patients.