Diabetes is associated with an inordinate burden of cardiovascular and renal disease, which is expected to accelerate during the next few decades. The relationship between the renin-angiotensin system (RAS) and diabetic macrovascular and microvascular disease is well established. The contribution of the tissue RAS in disease pathogenesis has recently been the focus of much interest, and has prompted investigators to explore the use of high-dose RAS inhibition with monotherapy or combination therapy to provide a more complete blockade of the actions of angiotensin II, beyond lowering blood pressure. There is now evidence to support this approach to maximize cardiovascular and renal protection. Optimal dosing strategies remain uncertain, but tissue specificity does not appear to be important if the doses of angiotensin-converting enzyme-I and angiotensin-receptor binders are high enough. The purpose of this review is to highlight our current understanding of the role of the tissue RAS in the pathogenesis of diabetic end-organ damage and ongoing strategies to interfere pharmacologically.