Sirolimus, a macrocylic lactone, blocks T-cell activation by a mechanism of action distinct from calcineurin inhibitors (CNIs). Therefore, it may be expected that sirolimus would display a safety profile without the vasomotor form of nephrotoxicity characteristic of CNIs. Initial studies in rodent models and in psoriasis patients showed that sirolimus alone did not impair renal function. Subsequently, two pivotal, randomized double dummy, phase III trials in human renal transplantation demonstrated that sirolimus exacerbated the nephrotoxicity of full doses of CNIs. Both pharmacokinetic and pharmacodynamic mechanisms have been implicated in the pathogenesis of this disorder. Subsequent experience has shown that cyclosporin A dose reduction, elimination, or avoidance mitigates these effects, particularly in patients distant from the transplant procedure. However, there is concern about recovery from ischemia-reperfusion injury. Animal models suggesting that sirolimus may delay recovery in this setting have been supported by non-randomized experiences at single centers, which have observed an increased incidence of delayed graft function among sirolimus-treated recipients. In contrast, large single- and multi-center studies have not confirmed this finding; impaired renal recovery has been observed in only occasional instances. Thus, present data indicate that sirolimus does not impair the function of an uninjured kidney, but whether the drug acts alone or potentiates conditions that delay recovery after ischemic injury remains to be established by large randomized trials specifically targeted to recipients at high risk for this complication.