Abstract: The shortage of donors restricts the development of organ transplantation. Xenotransplantation might act as an effective approach to resolve this problem. With the advancement of genome editing technologies as well as research and development of novel immunosuppressant, lots of breakthroughs have been achieved in the field of xenotransplantation. Nevertheless, a majority of researches are still in the preclinical stage. Recently, the success of the world's first genetically engineered pig-to-human heart transplantation has greatly inspired researchers. However, clinical xenotransplantation still faces an array of problems, including counteracting rejection, controlling inflammation, regulating coagulation disorder, improving physiological compatibility of xenografts, paying attention to the risk of interspecific infection, optimizing immunosuppressive regimen, screening donor genome editing types, selecting suitable recipients, modifying xenotransplantation guidelines, and awareness of public recognition, etc. In this article, these 10 problems were summarized, aiming to provide reference for promoting the clinical application of xenotransplantation.