PURPOSE OF REVIEW: To review the latest development in cardiac xenotransplantation in small and large animal models and related in-vitro studies. RECENT FINDINGS: With the recent introduction of ±1,3- galactosyltransferase gene-knockout (GT-KO) pig organs for xenotransplantation, improved cardiac graft survival has been obtained. However, this experience has demonstrated the importance of pig antigens other than Gal ±1,3Gal (Gal) antigens (so-called nonGal antigens) as targets for primate anti-pig antibodies. Several in-vitro studies have confirmed that, although the incidence and levels of anti-nonGal antibodies in nonhuman primates and humans are significantly less when compared with total anti-pig antibodies (i.e., anti-Gal + anti-nonGal), they can result in complement-mediated lysis of GT-KO pig cells. More recently, it has been demonstrated that regulatory T cells suppress the cellular xenogeneic response, thus potentially preventing or reducing T-cell-mediated rejection. The importance of thrombotic microangiopathy as a feature of the immune/inflammatory response and incompatibilities between the coagulation anticoagulation systems of pig and primate are receiving increasing attention. Development of GT-KO pigs transgenic for one or more antithrombotic euro;™ genes, for example, CD39 or tissue factor pathway inhibitor, may contribute to overcoming these problems. SUMMARY: Although GT-KO pigs have provided an advance over wild-type pigs as a source of organs for transplantation into primates, further genetic modification of GT-KO pigs is required to overcome the remaining immune barriers before a clinical trial of cardiac xenotransplantation can be contemplated. © 2008 Lippincott Williams & Wilkins, Inc.