Xenotransplantation exposes the recipient to known and unknown pathogens of the donor pig (donor-derived xenosis). A major effort has been undertaken to minimize the risk of transmission from the donor using specialized breeding techniques. With the exception of endogenous retroviruses and porcine lymphotropic herpesvirus, exclusion of known pathogens was successful and has eliminated a majority of donor pathogens. In the recipient, enhanced replication of many pathogens will be stimulated by the immune responses induced by transplantation and by the immune suppression used to prevent graft rejection. Infection of the graft may occur with unpredictable consequences due to the cross-species situation. Infectivity may be decreased as entry or replication is altered by missing receptors or inability to use the cellular machinery. Replication of organisms in the xenograft and the inability of the human host to respond to human pathogens in the context of a xenograft infection due to immune suppression, or the presentation of such pathogens in the context of pig instead of human major histocompatibility complex (MHC) could impair control of such infections. Recent data suggest that some human herpesviruses infections, such as human cytomegalovirus, may infect porcine tissue and are associated with a pro-inflammatory phenotype. This review focuses on human or recipient-derived pathogens and their potential harmful role in xenograft infection.