The incidence of diabetic nephropathy has declined these last decades, but diabetes mellitus still remains the commonest cause of end-stage renal failure, due to an increased prevalence of diabetes mellitus and a longer life expectancy for diabetic patients. The aim of this review is to describe the natural history of diabetic nephropathy and discuss the influence of many factors such as genetic and non-genetic progression promoters, hypertension, hyperglycemia, dyslipidemia, proteinuria and tobacco. Because only a comprehensive treatment strategy of these promoters will reduce the risk of end-stage renal failure, the inclusion of cardiovascular risk factors management and the screening of cardiovascular disease will further contribute to reduce the very high mortality of diabetic patients suffering of diabetic nephropathy.