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Hematopoietic stem-cell disorders such as sickle cell disease, thalassemias, and immunodeficiencies may be the most amenable diseases to consider for in utero treatment. Despite the theoretical advantages of in utero hematopoietic cell transplantation (IUHCTx) and its success in animal models, its efficacy in humans has been limited, and current research efforts are focused on understanding and surmounting the barriers to engraftment in the fetus. The observation that selective depletion of host hematopoietic stem cells (HSCs) prior to bone-marrow (BM) transplant results in high rates of engraftment in adult animals suggests that vacating host stem cell niches may improve chimerism after IUHCTx. Two recent studies in mice have implicated the maternal immune system in rejecting the in utero transplanted cells, and have rekindled enthusiasm in this field. Achieving donor-specific tolerance after IUHCTx has the potential to treat many hematopoietic disorders.