Background: Bioprosthetic heart valves undergo structural degeneration and calcification. Similarities exist in the histopathologic features of explanted bioprosthetic valves and rejected pig tissues and organs after xenotransplantation into nonhuman primates. The development of more durable bioprosthetic valves, namely from genetically modified pigs, could negate the need for the insertion of mechanical prostheses in children and young adults with the requirement for life-long anticoagulation and might avoid the need for reoperation in elderly patients. Methods: We reviewed the literature (MedlinePlus, PubMed, Google Scholar) through September 1, 2018, under four key terms: (1) bioprosthetic heart valves, (2) xenograft antigens, (3) immunologic responses to bioprosthetic valves, and (4) genetic modification of xenografts. Results: Advances in tissue and organ xenotransplantation have elucidated important immunologic barriers that provide innovative approaches to prevent structural degeneration of bioprosthetic heart valves. The current evidence suggests that bioprosthetic valves derived from genetically modified pigs lacking xenogeneic antigens (namely Gal, Neu5Gc, and Sda), termed triple-knockout pigs, would function considerably longer than current wild-type (genetically unmodified) porcine valves in human recipients. Conclusions: Preclinical and clinical studies to determine the safety and efficacy of triple-knockout porcine bioprosthetic valves will likely establish that they are more resistant to human immune responses and thus less susceptible to structural degeneration.