Application of high inspiratory oxygen concentrations is an established method to improve arterial oxygen content, oxygen transport and tissue oxygenation. However, in the past years a considerable amount of data have emerged challenging this approach: hyperoxic ventilation (ventilation with pure oxygen, HV) and subsequent hyperoxemia have been accused of inducing unfavorable effects on microcirculation and tissue perfusion, resulting in regional tissue hypoxia. Interestingly, these disadvantegous properties of HV seem to occur predominantly in patients with physiological hemoglobin concentrations and probably play a minor role in anemic patients. In animal experiments the effect of HV on tissue oxygenation and on outcome of several severe pathologic conditions essentially depends on the hemoglobin concentration: HV failed to have a considerable impact on survival of severe hypovolemia or methemoglobinemia (physiological hemoglobin concentration), whereas it convincingly improves outcome of severe normovolemic anemia. The present review discusses a perspective on the effects of HV at different hemoglobin concentrations and its potential to improve oxygen transport and tissue oxygenation especially during moderate and severe anemia.