In spite of current scientific advances, cardiovascular disease (CVD) remains the leading cause of death worldwide. Current strategies in cardiovascular prevention have succeeded in only limited risk modification. Pharmacological treatments both in primary and secondary prevention have shown to reduce cardiovascular risk and the fixed-dose combination therapy “polypill”, is hypothesized to synergize this effort. The polypill simply amalgamates multiple medications into one single pill. Several polypill formulations have been developed and recent trials have demonstrated in short-term feasibility, safety and efficacy in individuals with moderate cardiovascular risk. The benefits of the polypill may be apparent, but many challenges remain in the development of such a molecule. Trials are currently conducted to study the formulations, tolerability, compliance, regulatory requirements, cost and impact on lifestyle habits. This chapter aims to review the current evidence for polypill in the prevention of CVD.