Despite 2 decades of advances in therapy of diabetic patients, the prevalence of diabetic nephropathy among patients with diabetes has not decreased. However, large-scale multicenter studies have achieved great success in terms of the reduction of albuminuria, suggesting that albuminuria might not be an accurate surrogate marker for slowing the rate of renal function decline. It is important to be able to identify individuals at high risk for renal function decline, or ultimately, end-stage kidney disease (ESKD) and its associated cardiovascular disease (CVD). More sensitive early biomarkers, other than albuminuria and the estimated glomerular filtration rate (eGFR), should be required. Recently, serum concentrations of soluble tumor necrosis factor (TNF), receptor 1 (TNFR1), and TNFR2 have predicted future GFR loss and ESKD in patients of a wide variety of stages and both types of diabetes. Longitudinal interventional studies are needed to validate these biomarkers in a broad range of populations prior to implementation in routine diabetes management.