Hypertension frequently coexists with other cardiovascular risk factors, such as hypercholesterolemia, and their combination is associated with a greater rate of cardiovascular events. Recent clinical data support that treatment of hypertensive patients with a combination of antihypertensive and lipid-lowering therapies leads to a higher reduction in the incidence of cardiovascular events. In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), an optimal prevention of cardiovascular events was reached in patients who were randomly assigned to atorvastatin and the amlodipine treatment. However, the potential underlying mechanisms of these vascular protective effects are not fully elucidated. Because experimental studies have shown that statins and calcium channel blockers have antiatherosclerotic effects, the effect of atorvastatin alone or in combination with amlodipine was analyzed in the protein secretion profile of atherosclerotic plaques that were cultured ex vivo. In this respect, the addition of atorvastatin and amlodipine to atherosclerotic plaques normalized the levels of the different released proteins to that obtained from healthy arteries. This review highlights recent clinical and experimental studies that support that a combined treatment of hypertensive patients with both statins and calcium channel blockers could promote a higher reduction in their global cardiovascular risk profile and associated mortality. As an example, the application of a proteomic approach to assess the modulation by atorvastatin alone or in combination with amlodipine on the proteins that are released by atherosclerotic plaques has allowed the identification of novel therapeutic targets by which these drugs could promote their additive/synergic effects.