Transplantation can be a potent modality for the treatment of end-stage organ failure. However, the recipient’s immune system will recognize and respond to foreign antigens on grafts, which include both Major Histocompatibility Complex (MHC) and minor histocompatibility (mH) antigens, leading to graft rejection. To prevent graft rejection, most transplant recipients are put on a life-long, combined immunosuppressive drug/steroid therapy. Despite the side effects and toxicity, this treatment is not effective to prevent chronic graft rejection. Furthermore, since immunosuppressive drugs non-specifically inhibit the immune system, recipients have a higher incidence of infections and malignancy. Currently, a major goal of transplantation is to induce unresponsiveness or tolerance in recipients specifically to donor antigens expressed on grafts while maintaining a healthy and intact immune system against third-party antigens, such as viruses. Based on the immune mechanisms leading to graft rejection, many strategies have been developed for tolerance induction and been shown effective in animal models. These strategies include preventing the activation of anti-graft T cells by blocking costimulatory molecules, eliminating activated anti-graft T cells. More recent studies also suggest a role for regulatory T cells in the induction of transplantation tolerance.