Atherosclerotic lower-extremity peripheral artery disease (PAD) is increasingly recognized as an important cause of cardiovascular morbidity and mortality that affects more than 230 million people worldwide. Traditional cardiovascular risk factors, including advanced age, smoking, and diabetes, are strongly linked to an increase risk of PAD. Although PAD has been historically underappreciated compared to coronary artery disease and stroke, greater attention on PAD in recent years has led to important new epidemiologic insights in the areas of thrombosis, inflammation, dyslipidemia, and microvascular disease. In addition, the concept of polyvascular disease, or clinically-evident atherosclerosis in multiple arterial beds, is increasingly identified as a particularly malignant cardiovascular disease worthy of special clinical attention and further study. It is noteworthy that PAD may increase the risk of adverse outcomes in similar or even greater magnitude than coronary disease or stroke. In this review, we highlight important new advances in the epidemiology of PAD with a particular focus on polyvascular disease, emerging biomarkers, and differential risk pathways for PAD compared to other atherosclerotic diseases.