The only curative therapy for end-stage heart failure is orthotopic allogeneic heart transplantation. This therapy has extended the survival of patients worldwide but is limited due to the scarcity of donor organs. Potential alternative donor sources of organs for transplantation include genetically-modified (GM) large animal donors (ie, xenografts) and human organs developed in large animal hosts. These strategies utilize gene editing and somatic cell nuclear transfer technologies to engineer partially or completely humanized organs. Preclinical xenotransplantation studies of GM pig hearts into baboons have already provided an important clinical foundation, as two patients have received cardiac xenografts from GM pigs and have survived for up to 2 months. Additional issues need to be addressed in order for patients to survive more than 1 year, which would make these strategies clinically applicable. Thus, in combination with immunosuppression agents, xenogeneic and exogenic organ sources hold tremendous promise for an unlimited and transformative supply of organs for transplantation.