IN BRIEF Current therapeutic approaches are only moderately efficacious at preventing the progression of diabetic kidney disease (DKD). As the number of people with DKD continues to rise worldwide, there is an urgent need for novel therapies. A better understanding of the root causes and molecular mechanisms of DKD pathogenesis has enabled the identification of numerous new therapeutic targets, including advanced glycation end products, reactive oxygen species, protein kinase C, and serum amyloid A. Although experimental studies have illustrated the potential of such approaches, challenges in clinical translation remain a barrier in therapeutic development. Advances in preclinical safety and efficacy evaluations and improved delivery systems may aid in clinical translation of novel DKD therapies.