Advances in transplantation biology have enhanced the possibility of xenotransplantation as a therapeutic option for end-stage organ failure. The potential spread of animal-derived pathogens to the recipient and to the general population, termed "xenosis," is a potential complication of interspecies transplantation. Recognition of such infections will be complicated by the presence of new pathogens, new clinical syndromes, and altered behavior of these organisms in the immunocompromised xenograft recipient. Particular concern exists over the activation of latent viruses, including retroviruses, from xenograft tissues. Based on experience with human allogeneic transplantation, a strategy is proposed to stratify the risks of known pathogens from animal donors. Those pathogens considered most likely to cause human disease can be excluded prospectively from herds of animals developed for organ donation. Research is needed into the activation and behavior of retroviruses and other potential pathogens in xenotransplantation. Stringent, expert, peer review of clinical protocols must be performed for scientific merit and to enhance the safety of the recipient and of the community at large.