Interest in xenotransplantation derives from the documented need for more organs and tissues than can be expected from living or cadaveric donors. Although the barriers to xenotransplantation are formidable, the scientific rewards in addressing these problems have been significant. The first and most potent barrier to xenotransplantation is hyperacute rejection mediated by xenoreactive natural antibodies and serum complement. The majority of the xenoreactive antibodies appear to be directed at terminal galactose epitopes, especially gal alpha1-3 gal. Significant progress has been made in surmounting hyperacute rejection, and this has led to an examination of underlying mechanisms of delayed xenograft rejection. One of these delayed mechanisms concerns the potential role of graft recipient, natural killer (NK) cells. NK cells can cause variable, low-level cytotoxicity of xenogeneic endothelial cells in vitro that may be enhanced in the presence of xenoreactive IgG. The specificity of NK cell-mediated cytotoxicity appears to overlap with a major subset of xenoreactive natural antibodies. These cytotoxic interactions can be regulated by "humanizing" the endothelial cells through expression of the appropriate human MHC class I genes. More important, NK cells induce endothelial cell activation, which results in changing the nature of the endothelial cell surface from an anticoagulant surface to a procoagulant surface. These findings parallel those observed in allogeneic NK cell-endothelial cell interactions and suggest these important observations may be extended to NK cell-endothelial cell interactions in general.