Understanding pathogenetic mechanisms of diabetic nephropathy progression risk factors is important. Structural-functional relationship studies have increased our understanding of the glomerular, vascular and tubulointerstitial lesions evolution at various stages of diabetic nephropathy. Classical and more recently described lesions of diabetic nephropathy are discussed. Structural changes associated with progression toward proteinuria and GFR loss are summarized. The relationships of renal structure and function in diabetic nephropathy are best described by non-linear models which mimic the natural history of the disease, i.e., renal pathology develops in clinical silence but, once established, leads to proteinuria and GFR decline.