Endothelial damage and inflammation make a significant contribution to the pathophysiology of sickle cell disease (SCD) and the beta-thalassemia syndromes. Endothelial dysfunction and ensuing vasculopathy are implicated in pulmonary hypertension in the hemoglobinopathies and endothelial activation and endothelial-blood cell adhesion, accompanied by inflammatory processes and oxidative stress, are imperative to the vaso-occlusive process in SCD. Herein, we discuss the role that the endothelium plays in all of these processes and the effect that genetic modifiers and hydroxyurea therapy may have upon endothelial interactions. Therapies targeting the endothelium and endothelial interactions may represent a promising approach for treating these diseases.