Even with the availability of novel and efficacious antihypertensive agents, an insufficient number of hypertensive patients achieve their desired blood pressure (BP) target. This failure is partly due to the fact that many patients do not strictly adhere to their drug therapy and/or they report the presence of adverse effects. Traditionally, monotherapy is used as first-line treatment to achieve BP targets; however, when this fails, combination therapy is then required. In light of the need to attain BP goals, combination therapy (especially fixed-dose) is currently recommended. The main advantages of combination therapy over monotherapy are not only that of reduced dose, improved efficacy and reduced adverse effects, but also of target protection and reduced cardiovascular (CV) risk. Therefore, the development of single-administration drug combinations should also improve patient adherence to therapy and therefore help in achieving BP control. Among the various combinations available, calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors have been proven to be extremely effective, while also displaying good tolerability. Individually, both the third-generation CCB lercanidipine and the ACE inhibitor enalapril are effective antihypertensive agents. In addition, both of these agents also show other beneficial effects when administered as monotherapy. Of particular importance is the fact that when lercanidipine plus enalapril are administered in combination, they show synergism, thus providing added efficacy with reduced side effects. The present report provides an overview of the main clinical studies examining lercanidipine and enalapril administered as monotherapy, with particular focus on the potential renoprotective effects afforded by the fixed-dose combination lercanidipine-enalapril.