The structure of two current generation hemoglobin-based oxygen carriers designed to mitigate the vasoconstriction and renal toxicity associated with previous formulations is elucidated. Their potential advantages relative to, and in conjunction with, red cell transfusion will be described. The rationale behind growing interest in carbon monoxide therapy for sickle cell disease as an inhibitor of both polymerization and inflammation, and the specific advantages of delivering carbon monoxide through association with exogenous hemoglobin will be discussed.