The prevalence of hypertension is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and chronic cardiovascular disease (CVD), as well as in black and elderly subjects. In addition, these subjects have the lowest control of blood pressure (BP) among the hypertensive population, and also the risk of having a morbid or fatal cardiovascular event >20% in 10 years. For these reasons, aggressive control of BP to <130/80 mm Hg for these subjects is strongly recommended by National and International guidelines. To accomplish this goal, combination therapy with two or more antihypertensive drugs with a complementary mechanism of action is necessary. Drugs that block the renin–angiotensin system (RAS) in combination with a calcium channel blocker (CCB) and a diuretic have been shown to be the most effective combinations to accomplish this goal. However, this will require the administration of multiple drugs given separately, which will decrease the patient compliance and adherence to treatment. Poor patient compliance and adherence to treatment is a major factor for poor BP control. Several studies have shown that patient compliance is inversely related to the number of drugs being administered. To overcome this problem, several dual and triple-drug, fixed-dose combinations with a RAS blocker, a CCB and a diuretic have been developed and marketed, which are easier to administer, and have been shown to increase patient compliance and adherence to treatment. In this concise review, the effectiveness and safety of the fixed-dose, triple-combination of the RAS blocker olmesartan medoxomil, the CCB amlodipine besylate and the diuretic hydrochlorothiazide, as well as other similar combinations for the treatment of hypertension, will be discussed. These drug combinations have been shown to be effective, safe and well tolerated by most patients.