In human transplant recipients, incidental pathogen infections are common and present as a potential threat to the established immunological quiescence. We established a model of concurrent murine cytomegalovirus (MCMV) infection and transplant tolerance to study their reciprocal effects on each other. Ongoing studies suggest that acute as well as latent MCMV infection impair the efficacy of tolerance induction. This is likely accomplished via a number of cellular mechanisms including interfering with the function of host antigen presenting cells and differentiation and expansion of regulatory cell populations. On the other hand, in the presence of donor-specific tolerance, donor-derived MCMV reactivation can be effectively inhibited, suggesting that anti-donor immune response is a critical factor for the viral reactivation from its latent form. The precise cellular and molecular pathways underlying this reciprocal interaction are currently investigated in our laboratory. We anticipate that these results will have a significant impact on understanding the timing and choice for tolerance strategies in clinically practice, particularly as clinical transplant tolerance protocols are being developed and implemented in human transplant recipients.