Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities.