Anti-non gal antibodies are produced in xenograft recipients against multiple xenogeneic antigens. Studies in monkeys transplanted with pig organs lacking α-gal epitopes have suggested that anti-non gal antibodies mediate acute and chronic rejection of xenografts. This overview describes studies of these antibodies in patients who received xenografts and includes (1) an ovarian carcinoma patient receiving three intraperitoneal infusions of mouse fibroblasts in a gene therapy study, (2) orthopedic patients with torn anterior cruciate ligament replaced by a ligament made of pig patellar tendon, and (3) diabetic patients receiving fetal pig islet cell clusters xenograft together with a kidney allograft. Anti-non gal antibodies were found to be continuously produced as long as the xenograft was present in the recipient and were directed against a large number of pig proteins. Monitoring the immune response in the recipient of mouse fibroblasts indicated that the production of anti-non gal antibodies is much slower than that of the anti-Gal antibody, suggesting that they are generated by multiple B-cell clones, each initially comprising relatively few cells. Potent immunosuppression to prevent allograft rejection does not fully inhibit the production of anti-non gal antibodies. Much of this antibody response seems to be due to the differences in amino acid sequences between pig and human orthologous proteins as a result of evolutionary mutations. Overcoming the anti-non gal antibody barrier will require immunosuppressive agents that preferentially inhibit this immune response while maintaining protection against pathogens, or alternatively development of methods for induction of immune tolerance to xenogeneic pig antigens.