Whatever the aetiology and whatever the severity, the active management of respiratory failure habitually results in the administration of supplemental oxygen therapy. This review re-examines aspects of the optimization of such therapy. The oft-cited and well described risks of oxygen toxicity are revisited. Although no universal absolutes can be stipulated, the safe use of oxygen therapy is explored with particular reference to optimal oxygen targets. Specific attention is directed to the balance between the tolerable lower limits of systemic oxygenation and the putatively safe limits for titration of supplemental inspired oxygen fraction. Additional consideration is given to the emerging concept of permissive hypoxaemia. The attractiveness of this notion, and its potential role when the adverse effects of pursuing increased oxygenation combine to outweigh any benefit, has been enhanced by recent experiences with severe hypoxic respiratory failure arising from pandemic influenza viruses. Significant shortcomings remain in the existing definitions and descriptors of dysoxia, as well as the available technology for monitoring oxygenation. In clinical practice, oxygen displays a relatively narrow therapeutic index, and requires a careful balance of its benefits and risks. A detailed understanding of this ubiquitous therapy is obligatory in the optimal care of the critically ill.