Long-term CNI exposure may induce irreversible nephrotoxicity, resulting in progressive graft dysfunction. The CNI can also promote cardiovascular events and malignancies, which are the leading causes of premature death with a functioning graft. This discrepancy has prompted investigations into CNI retention strategies, which maintain adequate immunosuppressive effects without compromising safety Mammalian target of rapamycin inhibitors (mTORi) are new immunosuppressants that exhibit little or minimal nephrotoxicity. The dual immunosuppressive and antineoplastic properties of mTORi offer a distinct advantage for this class of drugs in the treatment of patients who receive kidney transplant. Nevertheless, major concerns associated with the de novo introduction of mTORi include the risk of AR, impaired wound healing, and prolonged delayed graft function (DGF), limiting the adoption of mTORi as a first-line immunosuppressant. The current state of the art with mTORi is the quest to discover the optimal immunosuppressive schedule that could guarantee kidney transplant recipients the lowest incidence of rejection and the best safety and long-term renal function. Thanks to all the basic, translational and clinical research achieved in the last twenty years, we now use mTORi as de novo immunosuppression in association with CNI at trough levels of 3–8 ng/mL. Another possibility is represented by the conversion of either CNI or mycophenolate (MPA) to an mTORi later on after transplantation. This can be beneficial in cases in which CNI- or MPA-related toxicity are evident, such as nephrotoxicity, tremor, leucopenia, diarrhea or CMV replication, which warrant a change in the immunosuppressive schedule.