Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large prospective clinical studies have shown that intensive glucose control reduces microvascular complications effectively among patients with diabetes, and the renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), activation of the RAS and protein kinase C (PKC), and stimulation of the polyol pathway, elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. Therefore, to develop novel therapeutic strategies that specifically target these metabolic and hemodynamic derangements is desired for patients with diabetic nephropathy. In this review, we discuss the molecular mechanisms of diabetic nephropathy and review the promising therapeutic targets for this devastating disorder.