Anemia and red blood cell (RBC) transfusions are common in critically ill and injured, trauma, and surgical patients. Tolerance of anemia is highly variable, depending on the presence of cardiovascular and other comorbid diseases that may diminish the hemodynamic response to a lower hemoglobin (Hb) level. The quest to define a minimum threshold Hb concentration at which patients achieve significant benefit to improve outcome has not yet been identified. Complications related to RBC transfusion are related to RBC storage and intrinsic properties of donor allogeneic RBCs, including bacterial contamination, transfusion-related acute lung injury, and transfusion-related immunomodulation. The best evidence related to transfusion-related outcome involves titrating transfusion requirements to parameters of severity of illness rather than arbitrarily defined Hb levels.