In Utero Hematopoietic Cellular Transplantation (IUHCT) is a promising intervention to treat a wide range of congenital disease. Through the presentation of donor cells to the immature immune system, mixed hematopoietic chimerism and donor-specific tolerance can be achieved. However, the failure of engraftment in prenatal recipients in which no immunodeficiency exists suggests the existence of a fetal immune barrier to transplantation. Although the possible barriers include effectors of the adaptive and innate immune system, our recent findings and ongoing investigations indicate that the barrier most likely resides in the developing NK cells. A chimerism level above a certain threshold during NK cell development is necessary to overcome rejection. Clinically, this transplantation barrier might also exist in early human fetal NK cells. Understanding the fetal immune barrier to allotransplantation is essential in advancing clinical application of IUHCT. Herein, we provide a short summary and new evidence for the earliest immune response to prenatal transplantation.