The current shortage of donors for allotransplantation has generated interest in the potential use of animal organs to meet increasing clinical transplant needs, ie, xenotransplantation. However, when phylogenetically distant species such as the pig are transplanted into unmodified primate hosts--discordant xenotransplantation--the grafts undergo a rapid rejection process characterized by edema, hemorrhage, and diffuse microvascular thrombosis. "Hyperacute rejection" as such is mediated by an IgM natural antibody directed against the galactose alpha(1,3) galactose epitope expressed on the endothelial cell surface of all mammals except old world monkeys, apes, and humans which collectively lack the galactosyltransferase enzyme necessary for antigen expression. Transplants between nonhuman primates and human recipients--concordant xenotransplantation--avoid hyperacute rejection, but nonetheless undergo "acute vascular rejection" and progressive microthrombotic injury. Acute vascular rejection is associated with endothelial cell "activation," loss of vascular integrity, and progressive thrombosis. Molecular strategies for avoiding xenograft rejection involve insertion of genes into the donor pig genome capable of modifying xenoreactive antigen expression and regulating antibody-mediated endothelial cell damage.