Sickle cell disease (SCD) is among the most common genetic diseases in the United States, affecting approximately 100,000 people. In the United States, SCD is characterized by a shortened life expectancy of only about 50 years in severe subtypes, significant quality-of-life impairments, and increased healthcare utilization and spending. SCD is characterized by chronic hemolytic anemia, vaso-occlusion, and progressive vascular injury affecting multiple organ systems. The pathophysiology is directly related to polymerization of deoxygenated hemoglobin, leading to a cascade of pathologic events including erythrocyte sickling, vaso-occlusion, tissue ischemia, and reperfusion injury as well as hemolysis, abnormal activation of inflammatory and oxidative pathways, endothelial dysfunction, increased oxidative stress, and activation of coagulation pathways. These multifactorial abnormalities have both acute and chronic clinical consequences across multiple organ systems, including acute pain episodes, chronic pain syndromes, acute chest syndrome, anemia, stroke and silent cerebral infarcts, cognitive dysfunction, pulmonary hypertension, and a wide range of other clinical consequences. Hydroxyurea was the only approved treatment for SCD for nearly 2 decades; in 2017, L-glutamine oral powder was approved for the prevention of the acute complications of SCD. During the last several years there has been a dramatic increase in research into treatments that address distinct elements of SCD pathophysiology and even new curative approaches that provide new hope to patients and physicians for a clinically consequential disease that has long been neglected.