Sickle cell anemia is a very complex disease. Vascular occlusion, the major event that accompanies SS, is itself a complex and multifactional process. Microvascular occlusion results in acute painful crises, whereas macrovascular occlusion seems to be the cause of organ failure. Understanding the basic pathophysiologic events of vascular occlusion may elucidate the clinical manifestations of SS, its natural history, and complications, and it may give new insights into preventive and curative therapy.