The purpose of this work is to emphasize the value of kidney biopsy in patients with diabetes mellitus and clinical renal impairment. Diabetes is the leading cause of end stage renal disease because diabetic nephropathy develops in 30 to 40% of patients. Multiple genetic predisposing conditions are involved in the development or not of a diabetic nephropathy, therefore supporting the existence of several factors in the pathogenesis of this disease. These predisposing conditions may also favor different other types of glomerulonephritis which can occur independently or in parallel with a diabetic nephropathy. All these renal diseases have different treatments, and therefore they must be correctly identified and managed accordingly. The processing of the kidney biopsy samples requires a very careful and highly qualified management to differentiate precisely the nature of each condition. In addition to the mesangial classical lesions, recent biopsy studies provided evidence that podocytes are injured very early in the diabetic nephropathy. On the other hand, transgenic mice models provide a unique opportunity to investigate the natural course of the disease. The paper underlines the main laboratory techniques required for this activity, and the main structural arguments to perform a satisfactory differential diagnosis.