For over a century, aspirin has been used for different indications, mainly as an antipyretic, analgesic, and anti-inflammatory agent. However, its cardioprotective properties were discovered only a few decades ago. Initially employed for its antiplatelet effect in secondary prophylaxis of cardiovascular (CVD) events, various large-scale trials have established the role of aspirin in primary prevention of CVD in people at high risk. This chapter summarizes the clinical trial data that demonstrated the efficacy of this drug in both secondary and primary prevention of cardiovascular disease events, the leading cause of death in the US. In addition, an account of the historical perspective on aspirin, its mechanism of action, optimal dose, adverse effects, interaction with other nonsteroidal anti-inflammatory agents, aspirin resistance, and current recommendations for its use in primary prophylaxis of CVD are presented.