Sickle cell disease (SCD) is caused by a mutation in the β-hemoglobin gene. This mutation results in a hemoglobin tetramer, sickle hemoglobin or HbS, in which the glutamate at position 7 of the β-globin chain is replaced by valine. Heterozygotes with sickle cell trait have a normal lifespan with few complications. In contrast, SCD is usually severe because, depending on the genotype of SCD, each red blood cell (RBC) has 50–95% HbS. SCD is most prevalent in parts of Africa, the Middle East, and India and spread throughout the world by slave trading and migration. Its pathophysiology is triggered by the polymerization of deoxygenated HbS resulting in erythrocyte (RBC) deformation or sickling. Damaged RBCs cause the clinical and laboratory features of SCD that include vasoocclusion, hemolytic anemia, inflammation, and reperfusion injury leading to widespread acute and chronic organ damage with reduced lifespan. Several common and many rare genotypes produce the phenotype of SCD. Most common are homozygosity for the HbS mutation, compound heterozygosity for HbS and HbC, and compound heterozygosity for HbS and a β-thalassemia mutation (Gladwin MT, Kato GJ, , 2021; Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, Disorders of hemoglobin: genetics, pathophysiology, clinical management. Cambridge University Press, Cambridge, 2009). HbS homozygotes have the most severe symptoms but phenotypic heterogeneity is the rule. The two major modulators of phenotypic heterogeneity are (1) coincident α-thalassemia, which decreases RBC density and HbS concentration, reducing hemolysis, and (2) fetal hemoglobin, which thwarts the polymerization of HbS (Steinberg MH, Sebastiani P , Am J Hematol 87:824–826, 2012; Steinberg MH, Blood 136(21):2392–2400, 2020).