Diabetic nephropathy (DN) is a well-described complication of diabetes mellitus and the leading cause of end stage renal disease (ESRD). Although increased albuminuria has been the gold standard for screening, data suggests that renal damage starts long before the onset of clinically apparent increases in macro and even micro-albuminuria. Clinical practice guidelines for the prevention of DN have been traditionally focused on the control of serum glucose, blood pressure and dyslipidemia, with some focus on the renin-angiotensin-aldosterone system (RAAS) as a main target for successful therapy. Recent evidence has led to a better understanding of the underlying mechanisms of the pathophysiology of this disease and suggests that various novels pathways can be targeted to delay and even prevent the progression of DN. Hence a more comprehensive therapeutic approach to therapy is on the horizon, carrying the promise for a more successful and impactful management. This review will highlight new insights into the pathophysiology, clinical aspects and future diagnostic and therapeutic modalities for DN.