Prenatal cellular therapy for the treatment of congenital disease has tremendous theoretical appeal. The replacement of defective cells with normal cells during specific periods of organ development and cellular ontogeny may have significant advantages over postnatal transplantation. Regulatory events during fetal development may favor the normal incorporation of transplanted cells and their proliferation. Early in gestation, immunologic barriers that are prohibitive to postnatal cellular therapy may not exist. Finally, successful prenatal cellular therapy could prevent prenatal and completely preempt postnatal complications of the disease. Several opportunities for prenatal cellular therapy exist that need to be explored experimentally and, when appropriate, clinically. Cells that may be transplanted to treat specific target diseases include the hematopoietic stem cell (HSC) CNS “stem cell,” hepatocytes, myoblasts or fibroblasts, and vascular endothelial cells. The rationale for transplantation may be replacement of a defective cell lineage with normal cells, as in the treatment of immunodeficiency diseases by prenatal hematopoietic stem cell transplantation, or the replacement of a deficient enzyme or factor by normal or genetically engineered cells, as in the treatment of inborn errors of metabolism by CNS “stem cells,” or hemophilia by hepatocytes. In addition, prenatal tolerance induction in preparation for postnatal cellular or organ transplantation may be a useful approach. This article discusses the prenatal transplantation of HSC as a successful paradigm for all prenatal cellular transplantation.