Diabetic nephropathy (DN) has become the most frequent cause of chronic kidney disease worldwide due to the constant increase of the incidence of type 2 diabetes mellitus in developed and developing countries. The understanding of the pathophysiological mechanisms of human diseases through a large-scale characterization of the protein content of a biological sample is the key feature of the proteomics approach to the study of human disease. We discuss the main results of over 10 years of tissue and urine proteomics studies applied to DN in order to understand how far we have come and how far we still have to go before obtaining a full comprehension of the molecular mechanisms involved in the pathogenesis of DN and identifying reliable biomarkers for accurate management of patients.