Potential benefit from the application of xenotransplantation as a remedy for donor shortage is limited by the intense antigenic challenge of the xenograft. Rodent models recently identified potential solutions to this problem, including xenospecific costimulatory blockade and new immunosuppressive therapies. Improved methods of conditioning to achieve mixed hematopoietic chimerism illustrate mechanisms for graft rejection and failure unique to xenotransplantation. New evidence from larger animal experiments illustrates the challenge of translating these lessons to models with clinical application.