The mechanisms by which GVHD and resistance to engraftment complicate bone marrow transplantation require further study and clarification. Yet the insights from the model systems presented here already have definite implications for human marrow transplantation. For example, the genetic basis of resistance to engraftment is clear. When marrow is transplanted into haploidentical recipients, resistance to engraftment and autologous host revovery is more likely to result than if donor and recipient were matched at the MHC. Engraftment could be increased in such haploidentical recipients by increasing the TBI dose in the transplant preparation regimen. Many centers have already increased TBI dose in an effort to prevent the recurrence of initial malignancies; such an increase would also aid marrow engraftment in haploidentical recipients. It has been suggested that T cell depletion of the marrow may also adversely affect engraftment and that the addition of T cells or T cell products back to the marrow might reverse such an effect. Experimental evidence for such approaches is not yet conclusive, however, and the re-addition of T cells to the marrow certainly increases the risk of GVHD. Our studies suggest that therapeutic strategies designed to ameliorate GVHD may have to account for NK phenomena. If T cells mediate GVHD via soluble factors such as IL-2 and γ-interferon which activate NK cells, then reversal of GVHD may require the disruption of NK function as well as T cell function. The use of monoclonal anti-T cell antibodies in vivo might therefore suffice as GVHD prophylaxis or as therapy in the very early stages of the disease, but anti-NK monoclonal antibodies might be needed to reverse an already established GVHD process. Further clarification of the origin of NK cells in GVHD will help direct therapeutic intervention. If the cells are of donor origin then removal of NK cells as well as T cells from the bone marrow could be attempted; if they are of host origin, then altering transplant conditioning regimens to decrease NK activity would likely prove useful. The in vivo model systems discussed here may serve not only to increase our understanding of the pathogenetic mechanisms attendant on bone marrow transplantation but may allow the evaluation of novel therapeutic strategies.