Blood pressure (BP) control remains insufficient worldwide, mostly due to poor adherence to treatments, clinical inertia, adverse effects and underuse of drug-combination strategies. Monotherapy and its uptitration have been long considered the first-line strategy in the treatment of hypertension, often leading to ineffective, time consuming and frustrating results. On the other hand, several studies have demonstrated that starting and continuing antihypertensive therapy based on a drug combination is associated with a greater reduction of BP, an earlier achievement of therapeutic goals and a higher proportion of patients achieving targets with favorable implications on cardiovascular events. However, one-fourth to one-third of hypertensive patients fail to achieve BP control even with dual combination therapies, requiring three or more antihypertensive agents. The aim of this review is to discuss the effects of triple-drug associations in terms of BP lowering and prevention of major cardiovascular events, also in high-risk patients. We also discuss available data on side effects and tolerability of triple combination therapy, and the advantages to use a single-pill formulation to promote simplification and adherence to therapy. The findings reported have provided the background for most recent international guidelines on hypertension that support the use of dual and triple combination therapy for most patients.