Proteinuria is both a marker and a mediator of progressive renal damage; higher levels are associated with greater cardiovascular and renal risk. At normal and low levels of proteinuria (in the microalbuminuria range), the rate of hard renal events (dialysis and doubling of creatinine) is much lower than the mortality rate. At higher levels of proteinuria, the renal event rate surpasses the mortality rate. In the overt nephropathy range (proteinuria > 0.5 g/L), patients who achieve lower proteinuria with therapy have improved hard renal outcomes, but this result has not been demonstrated in the micro-albuminuria range. For patients with more severe overt nephropathy, there is a basic rationale for additional blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade of this system and supramaximal dosing with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) have been demonstrated to reduce proteinuria in these patients more than therapy using the maximum recommended doses of these agents. However, evidence that dual blockade provides additional benefits for hard renal and cardiovascular outcomes is lacking, and only one study shows a benefit for supramaximal dosing. Both treatment strategies increase the risk for complications such as hyperkalemia. Therapy for patients with nephropathy should include treatment with the maximum recommended doses of an ACE inhibitor or ARB in addition to lowering blood pressure to target. For patients with overt nephropathy, more research is required on the role of dual therapy or supramaximal dosing to reduce hard renal and cardiovascular outcomes. Practitioners using either of these strategies to manage proteinuria should monitor their patients carefully.