Sickle cell disease (SCD) is a hereditary disorder that leads to the production of an abnormal hemoglobin, hemoglobin S (HbS). HbS polymerizes in deoxygenated conditions, which can prompt red blood cell (RBC) sickling and leaves the RBCs more rigid, fragile, and prone to hemolysis. SCD patients suffer from a plethora of complications, ranging from acute complications, such as characteristic, frequent, and debilitating vaso-occlusive episodes to chronic organ damage. While RBC sickling is the primary event at the origin of vaso-occlusive processes, other factors that can further increase RBC transit times in the microcirculation may also be required to precipitate vaso-occlusive processes. The adhesion of RBC and leukocytes to activated endothelium and the formation of heterocellular aggregates, as well as increased blood viscosity, are among the mechanisms involved in slowing the progress of RBCs in deoxygenated vascular areas, favoring RBC sickling and promoting vascular occlusion. Chronic inflammatory processes and oxidative stress, which are perpetuated by hemolytic events and ischemia-reperfusion injury, result in this pan cellular activation and some acute events, such as stroke and acute chest syndrome, as well as chronic end-organ damage. Furthermore, impaired vasodilation and vasomotor hyperresponsiveness in SCD also contribute to vaso-occlusive processes. Treating SCD as a vascular disease in addition to its hematological perspective, the present article looks at the interplay between abnormal RBC physiology/integrity, vascular dysfunction and clinical severity in SCD, and discusses existing therapies and novel drugs in development that may ameliorate vascular complications in the disease. © 2021 American Physiological Society. Compr Physiol 11:1785-1803, 2021.