The mammalian target of rapamycin inhibitors (mTOR-Is) sirolimus and everolimus represent a class of proliferation signal inhibitors with a wide spectrum of activities, including suppression of T-cell proliferation and reduction of tumor growth. In solid-organ transplantation, mTOR inhibitors are an option for maintenance immune suppression due to their relative lack of nephrotoxicity compared with the current backbone of most regimens, the calcineurin inhibitors (CNIs). This property, in conjunction with their unique pharmacology, allows mTOR-Is to be used as an adjunct or alternative to CNIs. Earlier studies of their use in de novo renal transplantation have delineated potential strategies for use of this class of drugs in groups of patients in whom mTOR inhibition may be useful. From recent kidney studies it appears that the time for introduction of mTOR-I therapy may be prior to the development of proteinuria or signiﬁcant graft deterioration. Consideration should also be given to the use of mTOR-Is in patients with or at high risk of post-transplant malignancy. Due to potential toxicities, knowledge of the adverse effects and pharmacokinetic proﬁles of mTOR-Is is necessary for proper management of patients receiving these agents.