Diabetic nephropathy (DN) is a serious complication of both type 1 and type 2 diabetes mellitus. The disease is now the most common cause of end-stage kidney disease (ESKD) in developed countries, and both the incidence and prevalence of diabetes mellitus is increasing worldwide. Current treatments are directed at controlling hyperglycemia and hypertension as well as blockade of the renin angiotensin system (RAS) with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Despite these therapies, DN progresses to ESKD in many patients. As a result, much interest is focused on developing new therapies. It has been over 2 decades since ACEIs were shown to have beneficial effects in DN independent of their blood pressure (BP) lowering actions. Since that time, our understanding of disease mechanisms in DN has evolved. In this review, we summarize major cell signaling pathways implicated in the pathogenesis of diabetic kidney disease as well as emerging treatment strategies. The goal is to identify promising targets that might be translated into therapies for the treatment of patients with diabetic kidney disease.