Atherosclerotic cardiovascular diseases remain the leading cause of morbidity and mortality in both developed and developing countries. Adequate treatment of vascular risk factors, such as low-density lipoprotein cholesterol and systolic blood pressure are known to reduce the future risk of cardiovascular disease in these patients. However currently, large treatment gaps exist among high-risk individuals, in whom the guidelines recommend concomitant treatment with aspirin, statin, and blood-pressure lowering agents. Combining aspirin, cholesterol, and blood-pressure lowering agents into a single pill called the cardiovascular polypill has been proposed as complementary care in the prevention of cardiovascular diseases in both intermediate- and high-risk patient populations. It is now a decade since the first recommendations to develop and trial cardiovascular polypills. The major scientific debate has been about the appropriate initial target population. This review article focuses on the potential role of fixed-dose combination therapy in different patient populations, outlines the pros and cons of combination therapy, and emphasizes the rationale for trialing their use. Current and planned future cardiovascular polypill trials are summarized and the pre-requisites for implementation of the polypill strategy in both primary and secondary prevention are described. The recent development of combination pills containing off-patent medications holds promise for highly affordable and effective treatment and evidence is emerging on the use of this strategy in high-risk populations.