Cardiovascular disease (CVD) is still the leading cause of death worldwide. The overall growth of this epidemic during the last decade is largely because of the increasing incidence of CVD in low and middle-income countries, where inadequate health policies, poor availability, and lack of affordable medications, as well as poor patient adherence to treatment all limit the efficacy of cardiovascular prevention strategies. Complementary to a promotion of healthy lifestyles, a fixed dose combination or a ‘polypill,’ containing two or more drugs addressed at controlling various risk factors, might reduce costs and improve patient accessibility and adherence to treatment. As of now, several clinical trials have shown that combination pills are well tolerated and decrease risk factors for CVD, with a projected improvement of end points by as much as 60–70% by reducing blood pressure and low-density lipoprotein cholesterol. However, uncertainty remains about changes of hard end points, long-term adherence, cost-effectiveness and the ‘medicalization’ of asymptomatic individuals who account for a large percentage of the world population. Because cardiovascular risk increases significantly for patients aged more than 50 years, it has been proposed to use a polypill to treat specifically all such patients. However, approach to be neither practical nor cost-effective, because it involves a large number of patients at low risk. Some investigators have suggested to incorporate the Coronary Artery Calcium Score with the Framingham Risk Score to identify a suitable target population of patients benefitting most from the polypill. Trials in progress will shed light on several issues currently debated and unresolved.