Healthy individuals are able to tolerate profound, short-term decreases in hemoglobin levels and oxygen saturation without serious consequences, but critically ill patients in respiratory failure lack the necessary reserve capacity to preserve tissue oxygenation. The development of progressive anemia in ICU patients has led to much interest and debate about transfusion practices, yet optimal hemoglobin levels and how they should be achieved remain unclear. Animal and human studies regarding critical oxygen delivery provide the rationale for optimizing hemoglobin levels and supporting cardiovascular function during respiratory failure. Theoretically, the oxygen-carrying benefit of RBCs should hasten recovery from respiratory failure, and transfusions would therefore be expected to shorten the duration of mechanical ventilation. However, evidence to the contrary has been reported. Controversies related to transfusions and their inability to improve outcomes suggest that further research regarding transfusion alternatives is needed, especially in anemic patients with respiratory failure.