Infection in transplantation results from interaction between the level of immune suppression and the epidemiologic exposures of the recipient. “Xenosis,” infection in xenotransplantation, may be increased beyond that of allotransplantation because: (1) the xenograaft may serve as a permissive focus of infection for donor‐derived organisms; (2) these organisms may be unknown or xenotropic; (3) microbiologic assays may be unavailable; (4) clinical syndromes due to such novel pathogens may not be recognized; (5) the necessary level of immune suppression may be greater than for allotransplantation; (6) donor‐derived organisms may acquire new (e.g., genetic) characteristics in the human host; (7) the presence of immune suppression and the high, intrinsic rate of infection may mask the presence of xenosis; and (8) MHC‐incompatibility may reduce the efficacy of the immune response within the xenograft. Because immunocompromised individuals are sentinels for infection by many types of novel infectious agents, and because there is some unknown level of risk that such pathogens will spread to the general population, microbiologic studies must be initiated in tandem with preclinical and clinical studies of xenotransplantation.