Recent clinical and experimental data suggest that nitric oxide (NO) may play a role in the pathogenesis and therapy of sickle cell disease. NO, a soluble gas continuously synthesized in endothelial cells by the NO synthase (NOS) enzyme systems, regulates basal vascular tone and endothelial function, and maintains blood oxygenation via hypoxic pulmonary vasoconstriction and reduced shunt physiology. These vital homeostatic processes may be impaired in sickle cell disease and contribute to its pathogenesis. Therapeutic NO inhalation exerts significant direct effects on the pulmonary vasculature to reduce pulmonary pressures and increase oxygenation that may prove beneficial in acute chest syndrome and secondary pulmonary hypertension. Delivery of NO bound to hemoglobin or in plasma may improve blood flow and hemoglobin saturation, and thus reduce ischemia-reperfusion injury. Other NO-related effects on adhesion molecule expression and fetal hemoglobin induction are of interest. While direct evidence for a clinical benefit of NO therapy in sickle cell disease has not been reported, studies are underway to determine if inhaled NO will reduce the substantial morbidity and mortality suffered by these patients.