Sickle cell disease is associated with considerable morbidity and premature mortality. Hematopoietic cell transplantation offers the possibility of cure and is associated with excellent results in pediatric patients receiving stem cell transplantation from a matched sibling donor. A reduced-intensity conditioning regimen has the potential to further reduce regimen-related morbidity and mortality. Improved understanding of the natural history of complications, such as stroke and pulmonary hypertension, effects of treatments such as hydroxyurea and blood transfusions, as well as the impact of transplantation on organ damage, are likely to influence the timing and indication of transplantation. Improvements in preparative regimens may enable the safe use of an alternative source of stem cells, such as unrelated matched donors, and further improve the applicability and acceptability of this treatment.