This issue of Hematology/Oncology Clinics, guest edited by Dr. Elliott Vichinsky, is devoted to Sickle Cell Disease, and focuses on pathophysiology of hemoglobinopathies, therapeutic targets, and new approaches to correcting ineffective erythropoiesis and iron dysregulation. Articles in this issue include Polymerization and red cell membrane changes; Overview on reperfusion injury in the pathophysiology of SCD; Regulation of ineffective erythropoiesis in iron metabolism; Altering oxygen affinity; Cellular adhesion and the endothelium; Arginine therapy; Role of the hemostatic system on SCD pathophysiology and potential therapeutics; Adenosine signaling and novel therapies; New approaches to correcting ineffective erythropoiesis and iron dysregulation; New approaches to correcting ineffective erythropoiesis and iron dysregulation; Fetal hemoglobin induction; Gene therapy for hemoglobinopathies; and Oxidative injury and the role of antioxidant therapy.