Transplant tolerance, which allows grafts—allogeneic cells, tissues, or organs—to be accepted without host immunosuppression, can be achieved in mice but not in primates. In this issue of Science Translational Medicine, Nadazdin et al. report that a high pretransplant frequency of graft-reactive memory T cells may inhibit the induction of transplant tolerance in nonhuman primates and lead to transplant rejection. Knowing the frequency of allograft-specific memory T cells in potential transplant recipients could aid clinical decision-making by guiding selection of the antigenic profile of the donor organ or by influencing the type of tolerance-induction protocol pursued.