It is hypothesized that tissue dysoxia and O2 debt are major factors in the development and the propagation of multiple organ failure in critically ill patients. Dysoxia is the result of an abnormal relationship between O2 supply (DO2) and O2 demand and translates into increased anaerobic metabolism and tissue and blood lactate concentration. First-line therapeutic strategies used to avoid the development of an O2 debt involve correction of cardiac output, haemoglobin, and O2 saturation in order to increase DO2 above its critical value. They are not sufficient, however, to ensure appropriate end-organ perfusion and oxygenation. The adequacy of cardiac output towards tissue metabolic requirements may be appreciated by venous-to-arterial and gut mucosal-to-arterial PCO2 differences. This review details these strategies and discusses their usefulness in current practice.