Summary The renin-angiotensin system (RAS) has key regulatory functions for blood pressure and fluid homeostasis. In addition, dysregulation of the system can have maladaptive effects to promote tissue injury in chronic diseases such as hypertension, heart failure, and kidney disease. These actions for the RAS to promote disease pathogenesis are especially apparent in diabetic nephropathy, the most common cause of end-stage renal disease in the United States. Evidence of a role for the RAS in diabetic nephropathy comes from studies in animal models and randomized clinical trials showing efficacy of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers to slow the progression of renal disease. Widespread applications of these therapies to a range of renal diseases may have contributed to the recent reduction in the incidence rates for end-stage renal disease. We provide a general review of the RAS and its role in diabetic nephropathy.