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We have been testing genetically engineered (GE) pig hearts and optimizing immunosuppression (IS) in non‐human primates (NHPs) since 2005. We demonstrate how we translated this preclinical investigation into a US Food and Drug Administration (FDA)‐approved clinical cardiac xenotransplantation. First, genetically engineered (GE) pig hearts were transplanted into the abdomen of NHP along with IS, which included anti‐CD20 and anti‐CD40‐based co‐stimulation blockade antibodies. We reported 945 days of survival of three gene GE pig hearts in NHPs. Building on this proof‐of‐concept, we tested 3–10 gene‐modified GE pig hearts (in order to improve the immunocompatibility of the xenograft further) in a life‐supporting orthotopic model, but had limited success due to perioperative cardiac xenograft dysfunction (PCXD). With novel non‐ischemic continuous perfusion preservation (NICP), using the XVIVO Heart solution (XHS), life‐supporting survival was extended to 9 months. We approached the FDA under an application for "Expanded Access" (EA), to transplant a GE pig heart in a patient with end‐stage non‐ischemic cardiomyopathy. He was without other therapeutic options and dependent on VA‐ECMO. A team of FDA reviewers reviewed our preclinical research experience and data and allowed us to proceed. This clinical cardiac xenotransplantation was performed, and the patient survived for 60 days, demonstrating the translational preclinical investigation of cardiac xenotransplantation from bench to bedside. The ultimate etiology of graft failure is currently a topic of investigation and lessons learned will progress the field forward. [ABSTRACT FROM AUTHOR]