Diabetic kidney disease (DKD) is a common, complex condition that has become a significant public health problem. The beneficial effects of intensive glycemic control in type 1 diabetes mellitus on development of DKD are proven; however, the evidence for nephroprotection in patients with type 2 diabetes is conflicting. Moreover, a strategy of intensive glycemic control increases the risk for adverse effects (hypoglycemic episodes) with no obvious impact on macrovascular events or mortality in recent large randomized controlled trials. The risk for hypoglycemia with intensive therapy is heightened in patients with significant renal dysfunction, due to decreased renal clearance of insulin. Establishing an ideal level of glycemic control in patients requires an individualized approach taking into account duration of diabetes and presence of coexisting comorbidities and pre-existing DKD. In this article, we review the available evidence from both observational studies and randomized controlled trials and provide suggestions about evaluating the potential benefits and harm from intensive glycemic control in patients. We also discuss how in the future, a personalized approach using biomarkers might help identify patients most likely to respond as well as those most susceptible to harm. We believe that using the optimal level of glycemic control in diabetic patients using a multi-pronged strategy will improve individual patient outcomes and decrease the overall burden of morbidity and mortality.