The morbidity and mortality associated with postnatal HSCT, toxicity of HSCT conditioning regimens, lifelong immunosuppressive therapy, and lack of compatible donors discourages many patients and physicians from utilizing postnatal HSCT as a treatment for congenital disease. Non-myeloblative in utero HSCT is now being considered as an alternate treatment with the hope that it will be more therapeutic with less toxicity to a wider spectrum of patients with congenital disorders. Prenatal stem cell transfer may eliminate many of the risks and hazards associated with postnatal HSCT, as the fetus may be less reactive than an immunologically mature individual such that tolerance to donor cells could be developed. GVHD and rejection of postnatal therapeutic grafts may be minimized thus reducing or eliminating altogether the need for postnatal myeloablation and immunosuppression. By using well-designed murine models such as the beta-thalassemic mouse outlined above, we believe we can determine the optimal conditions for non-myeloablative postnatal transplants with allogeneic or haplocompatible HSC following prenatal tolerance induction with these cells.