The most important task of clinical and experimental nephrology is to identify risk factors for progression of renal failure with the ultimate goal to counteract the dramatic increase of patients reaching end-stage renal disease. Recently, cigarette smoking has been recognized to be one of the most important remediable renal risk factors. The adverse renal effects of smoking seem to be independent of the underlying renal disease and the current evidence suggests a near doubling of the rate of progression in smokers vs. non-smokers. Cessation of smoking slows the rate of progression. Besides smoking, alcohol abuse has also been implicated as a renal risk factor. The present article reviews the current knowledge about the adverse renal effects of these legal drugs. Furthermore, the acute and chronic renal complications due to illegal recreational drugs is discussed. The impact of these drugs on the risk to reach end-stage renal failure is difficult to assess, which is mainly due to the fact that it is difficult to perform controlled prospective studies in substance abusers. According to estimates, 5-6% of new patients starting end-stage renal disease therapy may have opiate-use-related renal diseases in the USA--a figure which documents the magnitude of the problem. Thus, in any case of unexplained renal functional impairment substance abuse should be considered by the physician.