Triple therapy with lipid‑lowering, antihypertensive, and antiplatelet agents reduces the risk of recurrent cardiovascular fatal and nonfatal events, cardiovascular mortality, and total mortality in secondary prevention. In real life, however, effective implementation of these optimal treatments both in primary and secondary prevention is low, and thus their contribution to cardiovascular prevention is much lower than it could be, based on research data. One of the main barriers to the adequate implementation of these strategies is low adherence to the elevated number of pills, as adherence is adversely affected by the complexity of the prescribed treatment regimen, and can be considerably improved by treatment simplification. This review updates the findings provided by recent epidemiological and clinical studies favoring a polypill‑based approach to cardiovascular prevention. The increased prevalence of patients with multiple cardiovascular risk factors and comorbidities provides the rationale for a therapeutic strategy based on a combination of drugs against different risk factors in a single pill. Pharmacologic studies have demonstrated that different cardiovascular drugs can be combined in a single pill with no loss of their individual efficacy, and this favors adherence to and persistence of treatment, as well as multiple risk factor control. Recently, a randomized clinical trial SECURE (Secondary Prevention of Cardiovascular Disease in the Elderly) has shown a significant, 30% reduction in cardiovascular events, and a 33% reduction in cardiovascular death in patients after myocardial infarction treated with a polypill, as compared with usual care, thus supporting the polypill use as an integral part of any cardiovascular prevention strategy.