Oxygen therapy is primarily administered to alleviate arterial hypoxaemia and tissue hypoxia, and to facilitate aerobic cellular respiration. Hypoxaemia (PaO2 < 8 kPa [60 mmHg], SaO2 <92%) is associated with end-organ damage and adverse clinical outcomes, serving as a proxy measure for reduced intracellular PO2. Increasing the fraction of inspired oxygen should form part of an overall strategy to maximize tissue oxygen delivery. Permissive hypoxaemia represents a valid treatment strategy in a selected patient cohort. Oxygen is a drug and oxygen therapy is not benign, and oxygen administration at high, sustained doses (FiO2 >0.5, >12 hours) may cause oxygen toxicity. Observational studies in both mechanically-ventilated patients and survivors of non-traumatic cardiac arrest indicate an independent association between increasing hyperoxaemia and mortality. Oxygen therapy may additionally precipitate hypercapnic ventilatory failure in those at risk and oxygen should be administered to achieve a prescribed target SaO2 or PaO2 range, via adjustment of dose and delivery device. If no monitoring is available, hypoxaemia should be avoided by giving high-flow oxygen to achieve a FiO2 of near 1.0 with subsequent titration once oxygenation status is established.