The recognition of sickle cell disease as a chronic vasculopathy characterized by endothelial injury has led to new insights into complex biological processes and offers the potential for novel pharmacological treatments. Endothelial injury has been related to impaired nitric oxide (NO) homeostasis, inflammation, oxidative stress and coagulation activation. Therapeutic agents, especially those targeting multiple pathways of endothelial injury, including inflammation, thrombosis, oxidative stress and NO dysregulation are rational candidates for further exploration in sickle cell disease. This review will discuss novel drugs, specifically targeted at the endothelium, that are currently under investigation in sickle cell disease.