Albeit great efforts in reducing the burden of cardiovascular diseases (CVD), their prevalence continues to grow worldwide. Among the causes for this rising burden, the upcoming pandemic of obesity and diabetes further enhances the estimates of CV mortality and healthcare costs over the next decades. Nevertheless, advances in CVD treatment has increased life-expectancy, and future perspectives announce a growing aging population, with increasing comorbid conditions predisposing to CVD. Despite the emphasis on primary prevention, CV risk factors are still poorly controlled and a further need for CV drugs is upcoming. In chronic CVD such as hypertension, ischemic heart disease (IHD) and heart failure, the progressive use of multiple drugs is common and is recommended by international guidelines. However, the chronic use of five or more medications, defined as polypharmacy, has shown to be neither always efficacious nor safe. Polypharmacy is associated with an increased morbidity and costs. The use of multiple medications often leads to inappropriate drug use, underprescription, low adherence and side effects. In order to overcome these issues, a fixed-dose combination pill ('polypill') for the prevention of CVD has been recently proposed. A hypothetical meta-analysis estimated for this strategy a reduction of IHD and stroke by 88 and 80% respectively in people aged 55 or over. Such polypill can be cost effective and increase patient adherence. However, large randomized trials are required to define its impact on clinical outcomes. This review will focus on challenges of polypharmacy in CV medicine, illustrating potential options to face this emerging crisis.