The number of patients in need of an organ transplant is increasing, while the number of satisfactory sources of organs has declined in many countries [101]. The resulting shortage of human organs has spurred an urgent effort to investigate alternative therapies, including the use of animal organs, tissues and cells (i.e., xenotransplantation). Advances in genetic engineering have provided essential tools for the development of practical solutions to human disease. The area of xenotransplantation is no exception. In fact, the use of genetic therapies is especially attractive in the transplant setting as it offers an opportunity to manipulate the donor tissue rather than the recipient. This review will describe the obstacles in the clinical application of xenotransplantation and how genetic engineering might be used to address them.