Hypertension is a pressing global health issue, contributing to an increase in cardiovascular risk, as well as being the most common condition seen in South Africa. Lack of compliance with the prescribed therapy is one of the largest obstacles to achieving goal blood pressure in antihypertensive patients. The complexity of the drug therapy is a very important factor that is associated with noncompliance, as most patients require treatment with two or more drugs. The use of fixed-dose combination (FDC) therapy has various advantages, including simplification of the regimen, resulting in improved adherence. However, there are also disadvantages, e.g. the inability to provide individualised dose flexibility. This article provides an overview of available FDC therapy for hypertension in South Africa and the rational use thereof, by taking into account each combination’s complementary action, efficacy, safety and tolerability.