Clinical practice guidelines from many professional societies endorse renin-angiotensin system (RAS) antagonists as first-line antihypertensive agents in diabetes and chronic kidney disease, largely based on putative renoprotective properties that may be blood pressure (BP) independent. To evaluate the relevance of these recommendations to early stage, nonproteinuric nephropathy, studies of primary and secondary prevention of kidney disease were reviewed. Primary prevention studies were reviewed only for diabetic populations. Secondary prevention studies included hypertensive and normotensive, and diabetic and nondiabetic patients with microalbuminuria or low glomerular filtration rate. Overall, use of RAS antagonists as first-line agents does not appear to be as important as control of BP. To achieve protective levels of BP, multiple antihypertensive agents are usually required. Long-term studies with clinically relevant outcomes (death and loss of kidney function) are needed to clarify whether specific agents provide benefits beyond that of BP control in early stage, nonproteinuric nephropathy.