Tissue hypoxia is a key trigger for organ dysfunction. The maintenance of adequate tissue oxygenation is therefore of particular importance during major surgery. In this review, we discuss the physiological basis and the rationale underlying the recent concepts of perioperative oxygen therapy.Adequate tissue oxygenation is vital for optimal tissue healing in the surgical context. Nevertheless, the definitive proof for a beneficial effect of perioperative oxygen therapy with an increase in inspired oxygen has not been established. In contrast, optimization of oxygen delivery (DO2), using either or both fluid loading and inotropic supports, to prevent tissue hypoxia in relation to an increased oxygen consumption (VO2) could improve outcome. In this context, the use of central venous oxygen saturation (ScvO2), which reflects important changes in the DO2/VO2 relationship and of central venous-to-arterial carbon dioxide difference, to address adequacy of oxygen utilization, has shown promising results.Adequacy of oxygen delivery to tissue oxygen metabolic demand is essential during the perioperative period. The benefit of perioperative oxygen therapy is rather optimizing the DO2 than increasing inspired oxygen. Improving DO2 has been demonstrated in the perioperative period to reduce both morbidity and mortality. Adaptation of DO2 to O2 consumption using specific goals seems promising.