Current treatment and understanding of sickle cell disease require an appreciation for the complexity of its basic pathophysiology. The clinical manifestations of vaso-occlusion result from a dynamic combination of abnormalities in hemoglobin structure and function, red blood cell membrane integrity, erythrocyte density, endothelial activation, microvascular tone, inflammatory mediators, and coagulation factors. Existing and emerging therapies address each of these biologic alterations, individually and collectively. Examples include induction of fetal hemoglobin, modulation of erythrocyte hydration, augmentation of nitric oxide, chronic transfusion, stem cell transplantation, and gene therapy. Understanding the pleiotropic and epigenetic factors influencing disease phenotype may lead to more targeted application of these therapies.