We have explored the use of clinically relevant strategies to promote the engraftment of embryonic stem cells (ESCs) and differentiated cells derived from ESCs. A major problem with the planned and future clinical use of ESCs as well as differentiated progeny is that they are likely to be rejected by the immune system of the patient. In our studies we have utilized two approaches that have already been tested in the clinic. One is the use of total body irradiation and anti-thymocyte serum which we have successfully utilized in hundreds of patients successfully both with hematologic malignancies and those with kidney failure to promote engraftment of donor derived hematopoietic cells and in some instances with combined hematopoietic cells and kidney transplants. A second approach was to utilize normal T cell populations that have been shown by our group and others to regulate immune reactions, termed regulatory T cells. In our studies in murine models we were able to show that both total lymphoid irradiation and antithymocyte serum alone resulted in the engraftment of ESCs from a genetically different donor, however, these cells grew into tumors called teratomas. When we utilized differentiated progreny derived from the ESCs, which is much more similar to the proposed clinically situation, the combination of total lymphoid irradiation and antithymocyte serum or total lymphoid irradation and regulatory T cells promoted engraftment whereas these strategies alone did not. These studies demonstrate that using clinically relevant strategies that we can promote engraftment of differentiated cells derived from embryonic stem cells. These findings could have high relevance as these therapies are considered for clinical application.