It is now clearly evident after my enthusiastic predictions made in the early days following our first successes in curing by cellular engineering via BMT two highly lethal human diseases, namely, XLSCID and aplastic anemia, that BMT has emerged into an essential form of treatment and prevention for a variety of cancers ranging from high-risk leukemias, lymphomas, Hodgkin's disease, highly lethal primary immunodeficiency diseases, inborn errors of metabolism, complex hematological abnormalities, e.g., thalassemia and sickle cell disease and, more recently, complex autoimmune diseases. Further, using direct gene therapy, full cures of XLSCID have been achieved recently by A. Fisher et al. to cure infants, using the same basic methods tested initially by F. Anderson and M. R. Blaese in a rather futile effort to cure SCID that was due to ADA deficiency. We have recently also achieved by BMT a fully successful treatment of XHIM immunodeficiency in an infant which molecularly defined CD40 ligand gene sequences and corrected the deficient expression of the gene for CD40L both functionally and immunochemically. BMT also has the potential to cure immunodeficiency, not only in terms of susceptibility to infection, but also to close the door and inhibit other potentially fatal complications such as malignancies, a door which is open widely in several of the primary immunodeficiency diseases, e.g. WAS and SCID. The rapidly escalating developments and unfolding new insights on therapeutic approaches and treatment derived from studies on laboratory animals, especially in inbred mice, have contributed to a better understanding of the fundamental nature of autoimmune diseases and their etiopathogenesis. Thus, these laboratory studies have evolved continuously into potential new approaches to clinical practice, generating an entirely new perspective for major intractable diseases that may be addressed by BMT and other approaches to cellular engineering. More recently , addressing mice models, it has been possible to prevent GVHD by applying isolated TCD allogeneic BMCs and to prevent BMT-induced GVHD and graft rejection by using bone grafts, e.g. in MRL/ lpr lpr mice in which, together with BMT, recruitment of donor stromal cells is fostered which permits complete recovery of T cell function in a disease which otherwise is highly resistant to treatment by BMT alone. Another impressive achievement has been to use donor BMCs given via the portal venous route. These successful experiments have made possible the production of impressive long-lasting immune tolerance without using any irradiation or without recourse to immunosuppressants and permitted regular tissue transplantations to be realized in animals without rejection and with full immunologic tolerance. BMT has thus become a crucial component of scientific research on immune tolerance and graft acceptance and has become an increasingly powerful strategy for prevention of graft rejection and for treatment and prevention of a variety of intractable human diseases. Another encouraging direction for prevention and treatment of stable mixed chimerism has been the application of mixed BMT to correct the autoimmunities observed in the complex BXSB model as well as the NZW x BXSB (W/B)F1 model of idiopathic thrombocytopenic purpura, fulminating rapidly progressive renal disease, occlusive coronary vascular disease and fatal myocardial infarction. Mixed BMT as well as high dose stem cell transplantation alone has permitted prevention and cure of this complex highly lethal autoimmune disease associated with anticardiolipin autoantibodies. Thus, allogeneic mixed BMT can now be expected to offer an alternative for prevention and treatment of several autoimmune diseases which is not offered by syngeneic BMT. Acknowledgment: Aided by grants from USPHS-NIH, Institute on Aging #AG05628-16, and Pediatric Cancer Foundation to Children's Research Institute, All Children's Hospital.