Selective suppression of graft rejection while maintaining anti-pathogen responses has been elusive. Thus far, the most successful strategies to induce suppression of graft rejection relies on inhibition of T-cell activation. However, the very same mechanisms that induce allograft-specific T-cell suppression are also important for immunity against microbial pathogens as well as oncogenically transformed cells, resulting in significant immunosuppression-associated comorbidities. Therefore, defining the pathways that differentially regulate anti-graft versus antimicrobial T-cell responses may allow the development of regimen to induce allograft-specific tolerance. Recent work has defined a molecular pathway driven by the immunoregulatory protein coronin 1 that regulates the phosphodiesterase/cyclic adenosine monophosphate pathway and modulates T cell responses. Interestingly, disruption of coronin 1 promotes allograft tolerance while immunity towards a range of pathogenic microbes is maintained. Here, we briefly review the work leading up to these findings as well as their possible implications for transplantation medicine.