Sirolimus (SRL, rapamycin) is a potent immunosuppressive drug that binds to and inhibits mammalian Target Of Rapamycine (mTOR) kinase activity, a central controller of cell growth. In response to amino acids, hormones and growth factors, mTOR activates the translational machinery. By inhibiting mTOR, SRL reduces the translational process and T-cell proliferation in the mid-to-late G1 phase of the cell cycle. The antiproliferative effects of SRL are not limited to activated T cells. SRL has also been shown to block the cell cycle in various cell types such as epithelial renal cells, and many types of tumor cell lines. Since the approval by the US Food and Drug Administration and by the European agency, SRL has provoked great interest, as evidenced by the exponential increase in clinical studies. However, whereas preclinical studies failed to show any nephrotoxic effect on animal models, many clinical trials raised the possibility that SRL might be associated with renal adverse events. The evidence for SRL-associated early graft nephrotoxicity emerged from these results, and subsequent experimental data gave some explanations about the involved mechanisms. The aim of this review is to summarize the various renal adverse events reported in clinical studies and to present the experimental evidence for putative mechanisms of action for this SRL-induced nephrotoxicity.