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Sickle cell disease has been very well characterized as a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, with resulting red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. More recently, an independent spectrum of pathophysiology of blood vessel function has been demonstrated, involving abnormal vascular tone and activated, adhesive endothelium. These vasculopathic abnormalities are attributable to pathways involving hemolysis-associated defects in nitric oxide bioavailability, oxidative stress, ischemia-reperfusion injury, hemostatic activation, leukocytes and platelets. Vasculopathy of sickle cell disease has been implicated in the development of pulmonary hypertension, stroke, leg ulceration and priapism, particularly associated with hemolytic severity, and reported also in other severe hemolytic disorders. This vasculopathy might also play a role in other chronic organ dysfunction in patients with sickle cell disease. These pathways present novel targets for pharmacologic intervention, and several clinical trials are already under way. The authors present their perspectives of a workshop held at the National Institutes of Health in August 2008 on vasculopathy in sickle cell disease, along with meritorious future scientific questions on the topic of vascular complications of sickle cell disease.