Allogeneic stem cell transplant remains the only curative option for β-thalassemia major. In patients with good risk features it is reasonable to anticipate a greater than 90% chance of a successful transplant outcome. The conventional risk stratification system has limitations and alternative systems are being explored to better identify subsets that require innovative approaches. Several novel regimens have been evaluated to reduce treatment-related morbidity and mortality. There remain challenges in improving the clinical outcome of high-risk patients. There are limited data on the role of splenectomy before transplantation or optimal posttransplant chelation and care of these patients.