There is a critical shortage of allogeneic organs. A more elegant, long-term solution is to use transplantation from other species. However, unresolved questions exist concerning the susceptibility of xenografts to severe rejection and its mechanism. We have developed a humanized mouse model that allows the reconstitution of immunodeficient mice with human T and B cells and APCs in order to elucidate the immunological mechanisms of xenoresponse and achieve xenograft tolerance. These human cells demonstrate robust immune function, including graft rejection, proliferative T cell responses and class-switched antibody responses to protein antigens. Normal, polyclonal human T cells can also develop in porcine thymic xenografts that replace the human thymus graft in this humanized mouse model. These human T cells are specifically tolerant to the porcine thymus donor, suggesting an approach to achieving xenograft tolerance in humans.