Clinical studies and population-based analyses show that in patients with hypertension, the majority cannot control their blood pressure (BP) by treatment with a single antihypertensive agent. Combining agents from different antihypertensive classes with complementary modes of action significantly increases efficacy and is a treatment strategy recommended by European treatment guidelines, particularly in patients at high cardiovascular risk. The combinations of antihypertensive agents recommended by the European guidelines include an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). The single-pill combination formulation of the ARB olmesartan medoxomil plus the CCB amlodipine is an effective and well-tolerated treatment that provides greater blood pressure lowering and control than the component monotherapies and favours compliance by not increasing pill burden. Importantly, the efficacy and tolerability of olmesartan plus amlodipine is not affected by age, gender, hypertension severity, diabetes status, race or body mass index. Additional blood pressure lowering effects are observed with stepwise uptitration of olmesartan plus amlodipine with or without hydrochlorothiazide, with more patients achieving blood pressure goals. In addition, olmesartan plus amlodipine has demonstrated effects beyond BP lowering by showing beneficial effects on markers of inflammation, endothelial dysfunction and oxidative stress, as well as metabolic improvements and a reduction in new-onset diabetes incidence in hypertensive patients with metabolic syndrome.