Major efforts are being directed towards determining and modifying the glycosylated epitopes on pig vascular endothelial cells, against which human natural antibodies are directed. Genetic engineering techniques are being used in an effort to knock out or replace the major αgalactosyl (αGal) epitopes in mice, but to-date these have been only modestly successful in prolonging functional survival of such modified organs. Competitive glycosylation involving insertion of the gene for α1,2 fucosyltransferase results in reduction of αGal expression but also of presentation of hitherto cryptic antigens against which natural human antibodies are directed or could develop. The introduction of the gene for N-acetylglucosaminyltransferase III has been demonstrated to significantly reduce (αGal expression, and the intracellular expression of single chain Fv antibodies against α1,3 galactosyltransferase also represses this enzyme activity. Several other carbohydrate antigens have been identified that could act as targets for human natural antibodies, and these include Galα1-3Le(x), Hanganutziu- Deicher, Tn, and Forssman antigens. The alternative approach, namely, the depletion of the recipient's natural antibodies, is proving difficult, but techniques for inducing B cell tolerance are being explored. The induction of a state of mixed hematopoietic chimerism in αGal knockout mice has resulted in tolerance to the αGal antigen. Tolerance to the SLA antigens of miniature swine is also being attempted in baboons by the transfer of SLA Class II genes into baboon bone marrow cells. It is hoped that one or a combination of these approaches may overcome the problem created by the presence of pig antigens against which humans have xenoreactive antibodies.