Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, recurrent vaso-occlusive crises, progressive organ damage, and reduced life expectancy. Conventional therapies, including hydroxyurea, chronic transfusion programs, and emerging pharmacologic agents, primarily aim to reduce disease severity rather than provide a definitive cure. Hematopoietic stem cell transplantation (HSCT) remains the only established curative therapy for SCD, offering the potential for long-term disease-free survival through the replacement of the defective hematopoietic system with donor-derived stem cells that produce normal hemoglobin. In patients without HLA-matched marrow donors, umbilical cord blood (UCB) has become a viable substitute source of hematopoietic progenitors (CD34 +) for allogeneic stem cell transplantation. This review provides a comprehensive overview of the role of HSCT in the management of SCD, focusing on historical development, current indications, donor sources, conditioning regimens, outcomes, and complications. Advances in transplant approaches, including the use of matched sibling donors, unrelated donors, haploidentical transplantation, and UCB, have expanded eligibility and accessibility for patients who previously lacked suitable donors. Reduced-intensity and nonmyeloablative conditioning regimens have further improved transplant safety by lowering transplant-related morbidity and mortality, particularly in older patients and those with significant organ damage. Despite these advances, challenges such as graft-versus-host disease, graft rejection, infertility, and limited donor availability persist. Overall, HSCT represents a transformative therapeutic option for SCD, and ongoing innovations continue to refine its safety, feasibility, and global applicability.
