Abstract: Xenogeneic kidney transplantation is an important approach to alleviate the shortage of donor kidneys, but acute rejection remains the main obstacle in its clinical application. Xenogeneic acute rejection shows a clear temporal sequence: in the early stage, it is mainly mediated by antibodies and occurs through humoral rejection, with pre-existing antibodies targeting α-Gal and non-Gal antigens, activating complement and inducing thrombotic microangiopathy; in the later stage, it gradually transforms into a cellular rejection driven by infiltration of T cells and macrophages. In terms of diagnosis, donor-derived cell-free DNA can serve as an early non-invasive warning indicator, and histopathological biopsy remains the gold standard. In 2024, the Banff Working Group on Transplant Pathology of xenogeneic kidney transplantation released the first consensus on the pathological assessment of pig-human kidney/heart xenogeneic transplantation. However, this is currently only a reporting framework, and an independent grading system still awaits more clinical data. The treatment mainly focuses on multi-gene-modified donors combined with intensified immunosuppression, but it still faces challenges such as immature immunization regimens, the absence of monitoring systems and prominent infection risks. This article reviews the mechanisms, diagnostic monitoring, treatment strategies and clinical dilemmas of acute rejection, providing a reference for subsequent research.