Our goal is to identify clinically translatable strategies to induce tolerance to stem cell transplants. Host rejection of stem cells can occur by several mechanisms, all of which need to be circumvented. Towards this goal, in this past year we have laid the foundation for the use of natural killer (NK) cells in our animal models of bone marrow and embryonic stem cell transplantation to achieve stem cell transplant tolerance. We studied the immunogenicity of human and mouse embryonic stem cells with a focus on NK cells to tell us what hurdles stem cell based therapies have to overcome when encountering the patient’s immune system in the bloodstream. We found that a patient’s NK cells, which are part of the innate immune system, reside mainly in the bloodstream and kill cells which lack a molecule called major histocompatibility complex class I (MHCI), play a significant role in embryonic stem cell immunogenicity. This finding must be taken into consideration when applying regenerative therapies but may also be exploited beneficially to remove unwanted leftover pluripotent stem cells from stem cell-derived therapies. Furthermore, we studied the effectiveness of human NK cells to veto T and NK cell activity in vitro yielding findings that we now can apply to in vivo models of human stem cell transplantation rejection. Lastly, we have made progress in the use of specific subsets of mouse donor NK cells to improve their effectiveness in suppressing host T cells so that we can now translate those results into our mouse bone marrow transplantation model.