Despite the widespread availability of several effective classes of drugs, systemic arterial hypertension remains poorly controlled in the majority of patients worldwide. In this article, we discuss the different modalities and effects of combination therapy and possible future research questions. Treatment with a single antihypertensive agent can effectively reduce blood pressure in only a limited number of patients, while most require therapy with two or more agents to achieve target levels. As initial therapy, American and European guidelines suggest a combination of two antihypertensive drugs and the use of a third antihypertensive drug when hypertension is still uncontrolled. Initial combination therapy is recommended in high-risk patients for an immediate blood pressure response, improved tolerability and possibly increased patient adherence. In addition to the potential benefits of combining different drug classes with synergistic pharmacological and physiological actions, this approach is useful for increasing the patient compliance with treatment, in particular if provided at fixed doses in a single pill. The minimisation of side effects is critical for the long-term treatment of a largely asymptomatic condition such as systemic hypertension. Low-dose combinations of different drugs from classes with complementary actions may provide the best ratio of lower side effects and improved tolerability with a significant blood pressure reduction, particularly in high-risk patients. This approach could be aided by a multidisciplinary lifestyle intervention on risk factors.