Sickle cell disease (SCD) is caused by a mutation in both beta globin genes, resulting in chronic hemolysis and multiorgan disease that ultimately leads to premature death. Although hemoglobin S (HbS) polymerization and vaso-occlusion are central to the pathogenesis of SCD, overlapping pathways implicated in SCD-related endothelial dysfunction include hemolysis, defects in nitric oxide metabolism, ischemia-reperfusion injury, oxidative stress, increased cell-to-cell adhesion, and proinflammatory and coagulation mediators. Progression of organ-specific vasculopathy often precedes organ dysfunction and may provide targets for therapeutic intervention. SCD-related vasculopathies include, but are not limited to, moyamoya that often precedes cerebral infarcts or hemorrhage, proliferative retinopathy prior to loss of eyesight, pulmonary vasculopathy associated with pulmonary hypertension, and renal vasculopathy prior to the onset of chronic renal disease. This review evaluates evidence that SCD vasculopathy is a harbinger for organ dysfunction and reviews the potential for targeted antivasculopathy therapies.