Xenotransplantation represents a potential solution to the shortage of organs for transplantation. The recent advancements in porcine genetic modification have addressed hyperacute and acute vascular rejection; however, challenges persist with regard to delayed xenograft rejection. Porcine endothelial cells (pECs) represent a crucial target in the context of xenograft rejection, which is mediated by cytotoxic lymphocytes. It is crucial to comprehend the manner in which human natural killer (NK) cells and cytotoxic CD8 ⁺ T lymphocytes (CTL) recognize and target pECs in order to develop efficacious prophylactic strategies against rejection. The objective of the present review is to synthesize the existing knowledge regarding the mechanisms and techniques employed to modulate xenogeneic responses mediated by human NK cells and CTL. We will elucidate recent methodological advancements, debate potential novel strategies, and emphasize the imperative necessity for further research and innovative approaches to enhance graft survival.