Combination treatment of hypertension has been introduced almost 50 years ago, because of the marked blood pressure (BP) elevation of recruited patients in the early randomized controlled trials of BP lowering. However, in all subsequent trials combination treatment was per protocol anticipated irrespectively of the initial randomized treatment to ensure either a desirable BP lowering or a comparable level of BP reduction among arms. Beyond clinical trials, combination treatment is mainly used in the clinical practice to reinforce ongoing single-agent treatment to achieve hypertension control. Renin-angiotensin system inhibiting drugs are the cornerstone of combination treatment of hypertension because they have been repeatedly tested in clinical trials in combination with other agents either from the beginning or during the follow-up. Effective BP lowering following combination treatment depends on the activation of complementary pathophysiological pathways but different agents can stimulate a common mode of action more effectively. The rate of adverse events following combination treatment may be reduced because effects of each agents are reciprocally counterbalanced. Nevertheless, aggressive BP lowering independently of the implemented combination is associated with increase of treatment discontinuations. In the management of resistant hypertension, a fourth-line agent used on top of the failing triple (diuretic-based) combination is effective to control hypertension only in 50% of patients. At present, it is questioned whether combination treatment of hypertension should be used alternatively to monotherapy in newly-diagnosed hypertensive patients without marked BP elevation or at low cardiovascular risk. Selection between free and fixed-dose combination treatment should be individualized depending on clinical criteria.