Achieving optimal blood pressure (BP) control is the most important single issue in the management of hypertension, and in most patients, it is difficult or impossible to achieve target levels with one drug. Blocking two or more regulatory systems provides a more effective and more physiologic reduction in BP, and current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Fixed-dose combination therapy is an efficacious, relatively safe and cost-effective treatment option in most patients with essential hypertension. Of note, the once-daily administration of a fixed-dose enalapril/lercanidipine, by bringing together two distinct and complementary mechanisms of action, reduces BP effectively and has the potential for improved target organ protection relative to either class agent alone.