The first examples of hyperacute rejection of renal hemografts were seen almost 25 years ago when kidneys were transplanted to ABO incompatible recipients whose plasma contained antigraft isoagglutinins. Hyperacute rejection caused in sensitized recipients by lymphocytotoxic antibodies is similar in that the immune reaction triggers an acute inflammatory reaction that leads to widespread thrombotic occlusion and devascularization of the graft. The events after xenotransplantation between certain species are essentially the same. Potential strategies to avoid the precipitating antigen antibody reaction or to mitigate the resulting effector cascade are described.