Sirolimus (SRL) has been shown to improve long-term graft survival in several calcineurin inhibitor avoidance/minimization protocols. Although SRL has been suggested to reduce the progression of chronic renal graft damage and to prevent the development of neoplasia, two of the most prominent challenges in the field of transplantation, its use is significantly limited by an extremely high incidence of side effects. Some of the side effects are directly linked to the antiproliferative action of SRL, whereas the mechanisms underlying most of the undesired effects of the drug are still far from being clarified. Nevertheless, there is an increasing body of evidence linking most these drug-associated events to SRL dose. In addition, it is now possible to identify well-defined risk factors for most of these effects. Thus, to limit SRL-related side effects the two golden rules are (1) accurate selection of patients to be treated and (2) avoidance of high SRL doses.