Introduction: Cardiovascular diseases (CVD) remain the leading cause of death worldwide with an estimated 17.5 million deaths per year. Since its initial conception over a decade ago, the use of cardiovascular polypills has gained increasing momentum as a strategy to lower risk factor levels and prevent CVD. Several new data have emerged including the recent publication of the first outcomes trial using polypills. Areas covered: In this review, the authors summarize the current literature on the safety, efficacy, and cost-effectiveness of polypills for primary and secondary prevention of CVD, describe the current controversies in this field, and identify important areas for future research. The authors searched PubMed, CENTRAL, and ClinicalTrials.gov from inception till 25 June 2016 using the search term 'polypill.' Expert opinion: Cardiovascular polypills containing aspirin, statin, and one or more anti-hypertensive medications, along with lifestyle interventions, represent an attractive, safe, and cost-effective strategy for primary and secondary prevention of CVD. Future research efforts should focus on identifying patients who will benefit the most from the use of polypills, marketing several polypills with different components and doses, and developing novel regulatory strategies for making polypills more readily available in all countries worldwide.