In less than 50 years the field of organ transplantation has transitioned from an experimental concept to clinical commonplace. Notwithstanding the dramatic improvements in patient and allograft outcomes, chronic rejection and the complications from life-long immunosuppressive therapy remain significant problems. The induction of transplantation tolerance, indefinite allograft acceptance independent of chronic immunosuppressive therapy, remains the ultimate objective in transplantation. Many strategies have achieved tolerance to transplanted tissue in rodents; however, few, if any, have shown equal efficacy when tested in non-human primate transplant models or human patients. A critical distinction between specific pathogen-free mice and primates or human patients is the exposure of the latter to environmental pathogens and the resultant-acquired immune history. Recent data has shown that virally induced, alloreactive immune responses can provide a potent barrier to tolerance. In this review, we discuss one of the most robust methods for tolerance, the induction of hematopoietic chimerism as well as the influence of viral infections on the alloimmune response.