Diabetic nephropathy is now the leading cause of end-stage renal disease in the Western world. Renal disease develops secondary to long-standing hyperglycemia and hemodynamic alterations, which activate a common pathway that ultimately leads to the renal damage. Current strategies to treat diabetic nephropathy include optimization of glycemic control and treatment of glomerular and systemic hypertension. Although these strategies can slow the progression of proteinuria and decline in renal function, diabetic nephropathy remains a huge clinical problem. It is anticipated that future treatment modalities for preventing and treating diabetic nephropathy will involve drugs that modulate common pathogenetic pathways, possibly acting to inhibit both metabolic and hemodynamically induced forms of renal injury. These include inhibitors of growth factor and cytokine release or action, and inhibitors of intracellular second messengers. Although most of these agents have only been investigated in vitro, in animal experiments, or in relatively short-term human studies, these studies suggest that therapeutic strategies which involve a multifactorial approach may be more successful in the treatment of diabetic kidney disease than drugs which influence only one pathway.