Within a relatively short time span, a significant number of barriers to xeno-transplantation have been identified and potential solutions generated; however, the survival rates for pig-to-primate heart transplantation remain modest at best, with the longest functioning heterotopic heart transplant surviving only 99 days and the longest functioning orthotopic heart transplant surviving only 39 days. A great deal of improvement in immunological strategies will be needed to make xeno-transplantation a clinical reality. The most exciting prospect in the near term is the use of organs from homozygous alphaGal knockout pigs. The diversity of the biological pathways involved in the total spectrum of xenograft rejection, however, makes it highly likely that the clinical feasibility of xeno-transplantation will depend on a multipronged approach that incorporates the advantages of genetically eliminating the alphaGal epitope on hyperacute and acute xenograft rejection and the advantages of tolerance induction on cellular and chronic xenograft rejection.