The role of the renin-angiotensin system (RAS) in the regulation of blood pressure and the pathogenesis of both hypertension and renal complications involves an intricate interplay of genetic and environmental factors. In the case of diabetic nephropathy, the genes governing the RAS are an obvious choice in the search for contributing factors. These genetic components can reflect polygenetic mechanisms or a major gene effect. During recent years, polymorphisms of the genes governing both angiotensin converting enzyme (ACE) and angiotensinogen have been studied, with varying outcomes. Investigation of the interaction between ACE inhibition and the glycemic state yields equally interesting results. In healthy subjects on a high salt diet, the hyperglycemic state produced significant increases in renal plasma flow (RPF) in response to administration of the ACE inhibitor captopril. A similar study using the angiotensin receptor blocker (ARB) eprosartan demonstrated again that the agent had little effect on RPF in subjects in a normal glycemic state; however, when administered during a hyperglycemic state, a marked increase in RPF occurred. Implications for the prevention of nephropathy and endstage renal disease (ESRD) in diabetics with hypertension are significant. Until recently, pharmacologic intervention in the RAS has focused on the ACE step, with documented success being reported in the prevention of diabetic nephropathy and ESRD using ACE inhibitors. Despite this success, data suggest that greater therapeutic benefit might be accomplished by blocking the deleterious effects of angiotensin II at the receptor site. From a renoprotective perspective, the ARB appear to have tremendous potential in the management of hypertension.