The endothelium and red blood cells, although often studied in isolation, clearly interact to modulate nitric oxide (NO)– dependent vascular homeostasis, including basal blood flow, shear- or flow-mediated vasodilation, and hypoxic vasodilation. NO, produced by endothelial NO synthase (eNOS), plays a fundamental role in regulating blood flow. Recent data implicate a critical function for hemoglobin and the erythrocyte in regulating the bioavailability of NO in the vascular compartment. In fact, a delicate balance exists between endothelial NO formation, which is produced tonically and in response to shear stress (modulated by red blood cell mass), and NO scavenging by the erythrocytic hemoglobin. The scavenging of NO by hemoglobin inside an intact red blood cell is greatly diminished by diffusional barriers to NO– intrinsic to and surrounding the red cell. Compartmentalization of hemoglobin by the red cell also limits extravasation of hemoglobin dimers into the interstitial compartment. Intravascular hemolysis disrupts this balance by the release of hemoglobin from the red blood cell into plasma. This extracellular hemoglobin is then able to scavenge endothelialderived NO approximately 600-fold faster than erythrocytic hemoglobin, thus disrupting NO homeostasis. This may lead to vasoconstriction, decreased blood flow, platelet activation, increased endothelin (ET) –1– dependent vasoconstrictor activity (because NO modulates ET receptor expression to promote a vasodilator phenotype), adhesion molecule expression, and end-organ injury (1,2). This suggests a novel mechanism of disease for hereditary and acquired hemolytic conditions such as sickle cell disease and malaria. In addition to providing an NO scavenging role in the physiological regulation of NO-dependent vasodilation, hemoglobin and the erythrocyte may deliver NO as the hemoglobin deoxygenates.