ABSTRACTThe 2-month-survival of a terminally ill patient who received a genetically modified pig heart has demonstrated that cardiac xenotransplantation could provide a therapeutic option for patients who cannot receive a human organ. Genetic engineering to overcome transplant rejection mechanisms, coagulation dysregulation and overgrowth of xeno-hearts has been the key to this success. The concept of exogenesis – the replacement of specific cellular populations and tissue structures of a pig heart with human cells – is a promising extension of xenotransplantation because it could further reduce immunological and physiological obstacles. Additionally, in the aim of preventing the need for heart transplant, tailored pig models mimicking monogenic cardiac disorders have been developed to test new cellular and molecular therapies. Thus, genetically engineered pigs provide a powerful platform for xenogeneic, exogenic and endogenic restoration of cardiac function.