Xenoreactive natural antibodies are thought to be responsible for initiating the hyperacute rejection of porcine organs transplanted into primates. Progress has been made in recent years in the characterization of the specificity and functions of these antibodies. Xenoreactive natural antibodies recognize Gal alpha 1-3Gal, a carbohydrate related to the blood group A and blood group B antigens. The presence of Gal alpha 1-3Gal may not be sufficient to allow the binding of xenoreactive natural antibodies under physiological conditions; rather, the clustering of Gal alpha 1-3Gal determinants may dictate the extent to which xenoreactive natural antibodies attach to surfaces on which Gal alpha 1-3Gal is expressed. The predominant role of xenoreactive natural antibodies in the pathogenesis of hyperacute rejection in porcine-to-primate xenotransplantation involves the activation of complement. Complement activation is mediated by IgM, not IgG xenoreactive natural antibodies. Based on functional avidity, thermal binding optima, thermal liability and homogeneity of binding interactions, xenoreactive natural IgM appear to be members of a family of natural antibodies which includes isohaemagglutinins. The classification of xenoreactive antibodies and isohaemagglutinins into a family of antibodies may provide further insight into the nature and physiological functions of xenoreactive natural antibodies.