Aggressive secondary prevention is critical to improving long-term outcomes in patients with ischemic coronary artery disease, cerebrovascular disease, and peripheral artery disease. An essential component of successful secondary prevention is antiplatelet therapy, which in most patient populations consists of aspirin, clopidogrel, aspirin plus clopidogrel, or aspirin plus extended-release dipyridamole. As is true for any pharmacologic agent, benefits must be balanced with risks. For antiplatelet agents, the most important risk is excess bleeding, especially as emerging evidence suggests that excess bleeding is associated with adverse long-term outcomes; thus prevention and management of excess bleeding is critically important. In addition, recommendations for avoidance and management of minor adverse events are described so that patients maintain drug adherence. Overall, aspirin, clopidogrel, aspirin plus clopidogrel, and aspirin plus extended-release dipyridamole have favorable risk-versus-benefit profiles when used as recommended in appropriate patient populations.