Hematopoietic cell transplantation (HCT) has been used for more 30 years for the treatment of selected malignant and nonmalignant diseases. Traditionally, HCT for hematological disorders has relied on myeloablative conditioning before HLA-identical sibling bone marrow transplantation to correct the underlying hematological defect. Most children with hematological diseases who are referred to HCT have features that portend significant morbidity and early mortality. Among SAA patients who have HLA-identical sibling donors, younger patients with profound pancytopenia might be considered early for HCT. For others who lack sibling donors, patients who receive HCT from alternate sources have generally failed one or more courses of intensive immunosuppressive therapy and remain transfusion-dependent, some with hemosiderosis, red cell alloimmunization, and platelet transfusion refractoriness [44,46,48]. Currently, HCT for SCD is generally restricted to those who have experienced a significant sickle-related complication such as stroke, recurrent acute chest syndrome, or recurrent painful episodes [7,13]. In contrast, most reserve HCT in thalassemia for younger, Lucarelli class I, good-risk patients who have HLA-identical sibling donors, and veer away from older, high-risk thalassemics for whom transplantation is a riskier clinical intervention. For groups such as young adults with thalassemia major, HCT might become more widely applicable if its toxicity was reduced. Several approaches undergoing development include reduced-intensity conditioning and attempts to prevent GVHD. New methods to reduce the intensity and toxicity of conditioning as well as to use highly purified stem cells with the reduction in graft versus host disease may allow for the use of matched unrelated donors or haploidentical donors. This would serve to provide potentially more children who could benefit from stem cell transplantation with donors. These advances will hopefully lead to benefits for the majority of children who lack HLA-identical donors.