Sickle cell disease (SCD) is the most commonly inherited hemoglobinopathy in the United States. Blood transfusion is a critical part of the multidisciplinary approach necessary in the management of SCD; however, blood transfusions are not without complications. The successful use of transfusion as a treatment strategy in SCD requires the critical review and knowledge of transfusion methods, generally accepted indications, clinical situations in which transfusion generally is not considered, the selection of blood products, and strategies to prevent transfusion-related complications.