Red cell exchange transfusions remain an effective but possibly underutilized therapy in the acute and chronic treatment of sickle cell disease. In sickle cell disease, increased blood viscosity can cause complications when the hemoglobin exceeds 10 g/dL even if this is due to simple transfusion. Red cell exchange can provide needed oxygen carrying capacity while reducing the overall viscosity of blood. Acute red cell exchange is useful in acute infarctive stroke, in acute chest and the multi-organ failure syndromes, the right upper quadrant syndrome, and possibly priapism. Neither simple or exchange transfusions are likely to hasten resolution of an acute pain episode.