The recognition that the drivers of matrix accumulation is an appropriate therapeutic target for diabetic nephropathy is now accepted by the nephrology and pharmaceutical communities. Interventions focused around transforming growth factor-beta (TGF-beta) likely will be an important area of clinical investigation in the near future. Understanding the various pathways involved in stimulating TGF-beta in the diabetic kidney is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. In this review we highlight the major pathways involved in stimulating TGF-beta production by increased glucose levels and discuss the therapeutic implications thereof.