Xenotransplantation using porcine cells or organs may be associated with the risk of transmission of zoonotic microorganisms. Porcine endogenous retroviruses (PERVs) pose a potentially high risk because they are integrated into the genome of all pigs and PERV-A and PERV-B at least, which are present in all pigs, can infect human cells. However, PERV transmission could not be demonstrated in the first recipients of clinical xenotransplantation or after numerous experimental pig-to-non-human primate transplantations. In addition, inoculation of immunosuppressed small animals and non-human primates failed to result in demonstrable PERV infection. Nevertheless, strategies to reduce the possible danger of PERV transmission to humans, however low, could be of benefit for the large-scale clinical use of porcine xenotransplants. One strategy is to select pigs free of PERV-C, thereby preventing recombination with PERV-A. A second strategy involves the selection of animals that express only very low levels of PERV-A and PERV-B. To this end, sensitive and specific methods have been developed to allow the distribution and expression of PERV to be analyzed. A third strategy is to develop a vaccine capable of protecting against PERV transmission. Finally, a fourth strategy is based on the inhibition of PERV expression by RNA interference. Using PERV-specific short hairpin RNA (shRNA) and retroviral vectors, inhibition of PERV expression in primary pig cells was demonstrated and transgenic pigs were generated that show reduced PERV expression in all tissues analyzed. Intensive work is required to improve and to combine these strategies to further decrease the putative risk of PERV transmission following xenotransplantation.