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 landmark clinical studies have shown that intensive glucose control reduces the risk of the development and progression of diabetic nephropathy, and the blockade renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. However, diabetic nephropathy remains the leading cause of end-stage renal failure in developed countries. Therefore, to develop novel therapeutic strategies that specifically target diabetic nephropathy may be helpful for most patients with diabetes. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), and activation of the RAS and protein kinase C (PKC), 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. This article summarizes the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions that may prevent this devastating disorder even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.