Shortages in donor organs remain a significant hurdle to cardiac transplantation, resulting in deaths on the transplant waiting list and prolonged wait times of critically ill patients often supported by short term mechanical support devices. Sources of alternative donor organs to increase donor heart supply would be highly desirable. One such source is pig xenotransplants. To get to the point where this can become a clinical reality, novel genetic manipulations have to be performed including excision of potentially harmful genes such as those for porcine endogenous retroviruses (PERV) in a model that includes several genes knocked out using approaches such as CRISPR Cas-9 and several genes “knocked in” such as those that encode for human complement antagonists. In this way, the modified pig heart can be made less of a target for the human immune system which enabling the xenotransplant to inhibit human complement in the blood. To date, two living humans have received cardiac xenotransplants with survivals of up to 60 days, enabled with complex immunosuppressive regimens. Studies have also been conducted in decedents. Ongoing research is underway to learn from the first two recipients, identify living candidates for cardiac xenotransplantation and develop rational, effective immunosuppression to blunt the recipient immune response and address infectious disease issues.