The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus represents a class of immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2 and PI3K confers the anti-neoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are a valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft damage. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects (e.g., pulmonary toxicity, hematological disorders, dismetabolism, lymphedema) that need to be early diagnosed and treated to avoid severe illness in renal transplant patients. All these side effects are most of the time reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to increase their importance and specific therapeutic effects minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in CNI-free immunosuppressive protocol.