Sickle cell disease (SCD) is one of the best characterized human monogenic disorders. The development of molecular biology allowed the identification of several genomic polymorphisms responsible for its clinical diversity. Research on the first genetic modulators of SCD, such as coinheritance of α-thalassemia and haplotypes in the β-globin gene cluster, have been followed by studies associating single nucleotide polymorphisms (SNPs) with variable risks for stroke, leg ulceration, pulmonary hypertension, priapism and osteonecrosis, with differences in the response to hydroxyurea, and with variability in the management of pain. Furthermore, multigenic analyses based on genome-wide association studies have shed light on the importance of the TGF-β superfamily and oxidative stress to the pathogenesis of complex traits in SCD, and may guide future therapeutic interventions on a genetically oriented basis.