Sepsis is a generalized, usually infectious disease with a complex dsyregulated immune response and capillary leak. The leakage leads to a severe drop of blood pressure with hypoperfusion and sympathetic counterregulation. The lung is frequently involved either as a source of the inflammation or by emergence of an ARDS, both resulting into severe hypoxemia. The supportive therapy is used to stabilize the hemodynamics and to keep the target value partial pressure of arterial oxygen (PaO2) in the lower limit of normal. Pathophysiologically it is not plausible to define hypoxemia on the basis of PaO2 or SaO2, because the supply of the cells is determined by the amount of oxygen molecules. This is mirrored by the oxygen content (CaO2) and the hemodynamic transport, the cardiac output. As far as data about the hypoxic tolerance of organs are available, the critical value respective the threshold for anaerobic metabolism is 5-10 folds lower than values achieved by application of current guidelines. If CaO2 would be used as the target value, a lot of measures aiming for normoxia, which potentially harm patients, could be avoided. Among these measures are high, often toxic inspiratory concentrations of oxygen, high ventilation pressure, dangerous body position changes and excessive volume administration. It is not surprising, that there are no plausible data in the literature which have shown a positive effect for the target value PaO2 or SaO2. Studies are urgent needed to compare CaO2 as a target value to the standards in the current guidelines. Additional animal experiments should be done to get information on the critical range of CaO2, in order to translate these results into treatment strategies for intensive care unit patients with severe hypoxemia.