Allogeneic HSCT controls sickle cell disease (SCD)–related organ damage and is currently the only curative therapy available. Over the last 2 decades, HSCT has been limited largely to myeloablative matched sibling donor (MSD) procedures that are feasible only in a minority of patients. As the natural history of the disease has evolved, it is clear that subsets of patients with severe disease are at risk for sudden death, devastating CNS and pulmonary complications, and debilitating vasoocclusive crises. For these patients, the benefits of transplantation can outweigh the risks if HSCT can be safely and successfully performed with low early and late toxicities. This review describes advances and ongoing investigation of HSCT for SCD from the perspectives of recipient age and presentation, donor stem cell source, intensity of conditioning, family and medical perspectives, and other variables that influence outcome. Ultimately, HSCT should be viewed as a viable treatment option for SCD on par with other therapies for select patients who can benefit from the procedure.