Diabetes mellitus is acknowledged to be a group of metabolic diseases and heterogeneous in natural history, pathogenesis, response to treatment, and disease progression and remission. Diabetic nephropathy (DN) accounts for approximately 40% of all newly diagnosed cases of end-stage renal disease. The complexity of diabetes and its complications requires a broad-based, unbiased, scientific approach such as proteomics. Recently, proteomics (the systematic analysis of protein identity, quantity, and function) has been applied to the study of DN. Proteomic investigations into diabetic kidney disease have identified new mechanisms of diabetic renal pathology, as well as potential urinary markers of DN. Other current proteomic advances in understanding DN include identifying the role of advanced glycation end products in decreased mitochondrial respiration and also the rapid development of mass spectrometric methods for protein and peptide markers of DN development and markers to pharmacologic therapies. Proteomic analysis has only recently been applied to the study of DN, yet it has shown substantial potential.