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Confirmation of clinical tolerance requires the cessation of immunosuppressive drugs, which evoke immune reactivation and allograft rejection in all but the rare individuals who successfully transition into a state of operational transplantation tolerance. Therefore, the safe conduct of trials in transplantation tolerance requires two conditions: a sensitive and reliable means to identify individuals still being maintained on immunosuppression who are most likely to exhibit tolerance after immunosuppression is withdrawn and a noninvasive means that assesses the quality or robustness of the tolerant (TOL) state. Two recent studies attempting to identify a gene signature in peripheral blood of spontaneously TOL kidney transplant recipients made the unexpected observation that TOL, but not immune–suppressed transplant recipients, exhibited enriched B cells and B–cell transcripts in their blood. In concert with the emerging appreciation of a specialized subset of regulatory B cells (Bregs) that possess immune–modulatory function, these observations raise the possibility that Bregs play a critical role in the maintenance of tolerance to renal allografts in transplant patients. This review summarizes these recent findings and speculates on the relationship of Bregs to the maintenance of transplantation tolerance.