Simplified schematic of the primary pathogenic processes in SCD. SCD is caused by the inheritance of a mutated β-globin chain of hemoglobin (HbS). Polymerization of HbS in RBCs is the primary, fundamental lesion of SCD and leads to the pathognomonic sickle, crescent-like deformation of RBCs. Sickling of RBCs in turn leads to rheological, inflammatory, and cellular pathology via multiple interlinked pathways that affect every compartment of the vasculature. Hemolysis and endothelial dysfunction, sterile inflammation, hemostatic activation, oxidant stress, blood hyperviscosity, and cellular hyperadhesion have all been described as necessary components of vaso-occlusion, the primary pathology of SCD. All pathways are closely interlinked. For instance, sterile inflammation is the major determinant of cellular hyperadhesion, and hemolysis is responsible in large part for hemostatic activation and oxidant stress. Each pathway may be the predominant mechanism of vaso-occlusion in certain vascular beds or in response to specific triggers, and all pathways, as well as HbS polymerization, are further stimulated and enhanced by vaso-occlusion in a vicious cycle. For instance, vaso-occlusion leads to ischemia-reperfusion injury, a major determinant of oxidant stress.