Despite the existence of established, effective therapies for hypertension, new methods of blood pressure and cardiovascular risk reduction are still needed. Novel approaches are targeted towards treating resistant hypertension, improving blood-pressure control, and achieving further risk reduction beyond blood-pressure lowering. Modulation of the renin-angiotensin-aldosterone system (RAAS) provides the rationale for current antihypertensive therapies, including the relatively new agents eplerenone and aliskiren. Novel targets for antihypertensive therapy are also likely to be RAAS-related. The stimulation of angiotensin II type 2 receptors, or supplementation with renalase, could counteract the effects of angiotensin II type 1 receptor stimulation or catecholamine release. Combined angiotensin-converting-enzyme and neutral endopeptidase blockade decreases blood pressure, but is associated with a high incidence of angioedema. Aldosterone synthase inhibitors might improve tolerability in aldosterone antagonism. A (pro)renin-receptor blocker could prevent the deleterious angiotensin-independent actions of renin that are not inhibited by aliskiren. Finally, new minimally invasive surgical procedures have revived the concept of renal denervation, and could be a therapeutic option for patients with resistant hypertension. All of these strategies are exciting prospects, but which of them will prove valuable in clinical setting remains to be discovered.