The practice of transfusion for patients with sickle cell disease is changing. Diminished childhood mortality is resulting in greater patient longevity and a higher prevalence of chronic systemic complications. Many of these chronic complications, as well as several acute ones, are treatable with erythrocyte transfusion. Proactive or preventive uses for transfusion are being considered for selected patients. Immunologic phenomena, hemosiderosis, and risk for transmission of infectious agents are the three most noticeable risks associated with repetitive transfusion. Evolving work with alternative oxygen carriers and surface modification of erythrocytes is also promising and relevant for patients with sickle cell disease.