Cardiovascular diseases (CVD) account for one-third of annual global mortality. The aggregated benefits of concurrently controlling common CVD risk factors, such as dyslipidemia and hypertension, in people at overall risk for CVD is postulated to be more efficient than treating each individual risk factor to target. Administration of a polypill consisting of cholesterol-lowering (statins), antihypertensive, and antiplatelet agents together would simultaneously lower multiple risk factors, and applying such a population risk-reduction strategy would drastically reduce CVD incidence. This idea has generated much controversy and debate over the past decade. A few studies have emerged providing early evidence about the safety and efficacy of such a pill, and the results of ongoing and planned studies of outcome are eagerly anticipated. In this article, we review and interpret the existing evidence as well as explore the potential of a polypill for primary and secondary prevention of CVD.