Currently, hematopoietic SCT (HCT) is the only intervention that can restore normal hematopoiesis to provide a 'cure' in sickle cell disease. Yet, this treatment modality is used sparsely - a total of less than 400 transplants are reported in the Center for International Blood and Marrow Transplant Research database despite 70 000 afflicted in the United States; 88% of transplants are from HLA-matched sibling donors and 84%are <16 years of age at transplant. Overall survival at 3 years is over 90% after HCT in the young but 62% in adult HCT recipients due to increased disease and transplant-related morbidity. The decision and timing of HCT is a dilemma for physicians and families due to the need to consider HCT before severe organ damage in a disease that is generally not fatal in children with adequate supportive care. From the transplant physician's perspective, however, advances in the ability to identify well-matched donors, supportive care and promising conditioning regimens with low toxicity and transplant complications support the development of new HCT trials for sickle cell disease as the risk/ benefit ratio can be balanced better. With the recognition of new predictors of early mortality, the anticipation of extensive and expensive life-long medical support, and the poor quality of life despite medical care, the scales tip in favor of HCT. This is prime time for the development of careful unrelated donor HCT trials for sickle cell disease. Research efforts targeting HCT will need to be directed at seeking safe and effective transplant methods applicable to all patients who might derive benefit.