A de novo calcineurin inhibitor avoidance regimen based on sirolimus has been successfully used worldwide; demonstrating improved renal function from 1 to 5 years. This includes use of an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids. This combination has a somewhat different side effect profile and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring, especially the first 6 months posttransplant. Experience has also demonstrated that delaying the introduction of sirolimus in patients considered at high risk for early mammalian target of rapamycin associated complications will optimize these results. For such recipients, the initial use of a calcineurin inhibitor drug for 2 to 4 months is preferred, followed by conversion to sirolimus. The late withdrawal of steroids may be possible, but awaits further evaluation in randomized controlled trials.