Allogeneic hematopoietic stem cell transplantation (HSCT) still remains the only curative treatment for patients with thalassemia major (TM). However, HSCT is associated with a non-negligible risk of both transplantation-related mortality (TRM) and morbidity. Great interest and relevant expectations have been raised by the introduction in the clinical practice of reduced-intensity preparative regimens, which may represent an effective strategy to reduce the toxicity of transplantation and may also help reduce the incidence of late effects. Although some reports have documented the feasibility of using reduced-intensity preparative regimens for successfully treating patients with TM, a high incidence of graft failure has been frequently reported. Recently, treosulfan-based myeloablation has been demonstrated to be associated with limited extra-medullary toxicity and a high rate of sustained donor engraftment. This novel approach is a promising alternative for reducing the risk of life-threatening complications and increasing the number of TM patients successfully cured with an allograft.