The long-term use of analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) results in distinct renal abnormalities. The principal lesions induced by both groups is a tubulointerstitial nephropathy which, in the case of analgesics, results in renal papillary necrosis and progressive chronic renal failure. The tubulointerstitial nephropathy associated with NSAIDs presents with massive proteinuria and is generally reversible on discontinuation of the inciting NSAID. The scope and magnitude of the renal syndromes associated with these agents and the risk of renal failure associated with their use remains to be clearly defined. This review focuses on the current understanding of the processes involved and the initial defects in renal function that occur, with the goal of early detection and potential prevention.