In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, significantly contributes to burden of morbidity and increases their risk of a premature death. Indeed, excess mortality associated with diabetes is almost entirely confined to those with chronic kidney disease. Similarly, myocardial infarction and stroke are over 2-10 times more common in diabetic patients with kidney disease than in those without normal renal function. The efficiency of current management strategies for the treatment of diabetic nephropathy, even in optimal combination, is partial, at best. Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (smarter) therapeutic interventions against oxidative stress, inflammation, endothelial dysfunction, AGE accumulation, activation of PKC, the renin angiotensin system, and other key pathogenic pathways. Moreover, shifting the focus to the primary prevention of kidney disease in diabetes, rather than simply its treatment is vital for the ongoing health of the 300 million patients with diabetes worldwide.