SUMMARY Understanding mechanisms that regulate nitric oxide (•NO) function in the vascular compartment is critical in the context of transfusion‐based therapeutics. The role of hemoglobin (Hb), either cell‐free or encapsulated within the erythrocyte, has received much attention owing largely to the rapid rate of reactions between •NO and either oxy‐ or deoxyheme. In this review, we discuss the different mechanisms proposed by which •NO reactions with Hb are controlled under physiological conditions and which involve both preventing •NO‐scavenging by Hb and erythrocyte (and Hb)‐dependent stimulation of NO‐signaling. How these mechanisms may be utilized therapeutically in the design and application of Hb‐based oxygen carrier therapeutics is also discussed.