Hypertension is a common disorder linked to increases in cardiovascular mortality and morbidity. Effective treatment decreases this excess mortality. Therapy with a single antihypertensive agent fails to achieve blood pressure goals in up to 75 % of patients. Compared to monotherapy, combination antihypertensive therapy, especially with fixed-dose (single pill) formulations, may more effectively control blood pressure and improve medication persistence while decreasing adverse effects, healthcare costs, and physician therapeutic inertia. Certain combinations, such as a calcium channel blocker and angiotensin converting enzyme inhibitor, have been associated with similar or fewer adverse effects and better outcomes than other combinations. In contrast, other combinations such as thiazide diuretics and β-blockers may cause more adverse effects than monotherapy. When choosing a thiazide diuretic, chlorthalidone is preferable to hydrochlorothiazide, given better efficacy and cardiovascular outcomes. Initial combination antihypertensive therapy may benefit patients with stage I or II hypertension and more widespread use should be encouraged.