Blockers of the renin-angiotensin-aldosterone system (RAAS) have an established role in the management of hypertension, cardiovascular and renal disorders. Since the RAAS can escape blockade from a drug with a single mechanism of action, it has been proposed that combining RAAS blockers with complementary mechanisms of action may provide incremental benefit. Studies utilizing various combinations of RAAS blockers have demonstrated an advantage over monotherapy in patients with resistant hypertension, heart failure and nephropathy, while failing to show benefit in patients at high risk of cardiovascular events (e.g., the ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) and in those after a myocardial infarction. In this article, we discuss the rationale for the use of multiple blockers of the renin-angiotensin system and the evidence for and against such an approach in particular patient populations by reviewing relevant clinical trials that have addressed this hypothesis. © 2011 Future Medicine Ltd.