Thalassemia major is characterized by severe anemia dependent on red cell transfusions from infancy. Conservative management requires a safe source of compatible blood throughout life, strategies to combat iron overload, monitoring and treatment of transfusion-related complications, and management of cardiac and/or hepatic dysfunction from iron accumulation. Complications can result in premature morbidity and mortality. Stem cell transplantation is curative, but outcomes depend on the availability of a histocompatible donor, recipient age, and disease-related complications. Successful transplantation requires stable donor engraftment and donor-derived erythropoiesis and a low incidence of graft-versus-host disease, organ toxicities, and mortality. This translates to a cure with good quality of life and life span. Since recipients are at a high risk for graft rejection (prior transfusions, immunocompetency), myeloablative transplants have been the norm. Recent modifications to standard preparative regimens have significantly reduced transplant toxicities, resulting in >80% disease-free survival in children. Aiming to further reduce regimen-related toxicities, such as veno-occlusive liver disease and sterility, a recent trial explored reduced-intensity conditioning in unrelated donor (URD) transplants utilizing marrow or umbilical cord blood in patients without suitable familial donors. This report summarizes advances in URD transplantation for thalassemia, focusing on conditioning regimen nuances.