Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.