Peripheral arterial disease (PAD) of the lower extremities is a common and potentially life-threatening manifestation of systemic atherosclerosis. Significant PAD is identified by an ankle brachial index (ABI) < 0.90; its presence is strongly associated with the major modifiable cardiac risk factors. Early detection and treatment of asymptomatic PAD is a current focus of numerous cardiovascular guideline organizations as less than a third of patients report typical claudication symptoms. This has created an ever-increasing treatment gap, whereby millions of eligible patients are inadequately treated. Risk factor management including exercise, smoking cessation, and aggressive treatment of lipids and blood pressure are essential in PAD patients. However, life-long antiplatelet therapy provides additional reductions in vascular events beyond aggressive risk factor management. The use of aspirin as well as more potent antiplatelet therapies such as thienopyridines holds promise for reducing atherothrombosis in this very high-risk population.