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Mammalian or mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that plays essential roles in cell growth, proliferation, metabolism, and survival. Increased activation of the mTOR pathway is observed in patients and animal models of renal transplant rejection, autosomal dominant polycystic kidney disease, renal cell carcinoma, diabetic nephropathy, lupus nephritis, and angiomyolipoma. Agents that inhibit mTOR, such as sirolimus and everolimus, are incorporated in immunosuppressive regimens to prevent renal allograft rejection and are often used to facilitate calcineurin inhibitor minimization or to reduce the incidence of tumor recurrence. There are data from basic or animal studies to suggest that sirolimus and its analogs may also benefit patients with autosomal dominant polycystic kidney disease and metabolic- or immune-mediated renal diseases through its ability to reduce glomerular hypertrophy, renal parenchymal inflammation and fibrosis, but translation into clinical use has proved challenging. This review summarizes the current understanding of mTOR signaling pathway under physiological and pathological conditions and recent findings on mTOR inhibitors in the management of kidney transplantation and nontransplant kidney diseases.