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The inhibition of mTOR promotes immune tolerance in mouse models of transplantation, by favoring the expansion of regulatory T cells over effector T cells. However, attempts at inducing immune tolerance with the mTOR inhibitor (mTOR-I) in humans have so far failed. We herein review the immunological obstacles that need to be overcome in order to translate mTOR-I-related tolerogenic properties into the clinic.Our knowledge of regulatory T-cell biology has exploded over the past few years, providing clues to explain the complex impact of prolonged mTOR inhibition on the biology of regulatory T cells. Furthermore, recent data have shed light on the unexpected pro-inflammatory burst observed in some transplant recipients treated with mTOR-I. We propose that the exposure of an organism to pathogens determines the immunodominant effect of mTOR-I, altering the immune system from a state of tolerance in inbred animals to a state of infection-triggered enhanced inflammation in humans.Recent advances in the understanding of the pleiotropic effects of mTOR-I on the immune system are paving the way to new therapeutic avenues. Future mTOR-I-based tolerogenic protocols should counter the mTOR-I-related inflammation in order to selectively promote expansion of stable regulatory T cells. We herein envisage promising therapeutic perspectives.