One of the major goals of transplantation biology is to overcome transplant rejection without the need for life-long immunosuppression. Over the last several years, fundamental advances in our understanding of the immune response to allogeneic and xenogeneic antigens have stimulated a great deal of interest in the possibility of using gene therapy approaches to overcome the host response leading to transplant rejection while alleviating the need for non-specific immunosuppression. Here, we review recent progress in the field on the use of gene therapy to induce transplantation tolerance to donor organs and tissues.