Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. The progression of kidney disease in patients with diabetes can take many years, and interventions such as glycemic control, blood pressure control, and inhibition of the renin-angiotensin-aldosterone system have been shown to slow this progression. Despite the implementation of these strategies, the number of patients with diabetes that ultimately develop end-stage renal disease remains high. Recent investigation has focused on the optimization of renin-angiotensin-aldosterone system blockade in patients with diabetic nephropathy using combinations of drugs that target this pathway. Additional investigation has focused on the potential of novel therapies that either target various pathways upregulated by hyperglycemia or other targets believed to promote progression of diabetic nephropathy such as the endothelin system, inflammation and vitamin D receptors. This review article addresses some of the well-established principles regarding the progression and accepted management of diabetic nephropathy and includes current updates on the most recent clinical research trials exploring novel therapeutics in this field.