Peripheral artery disease (PAD) is a highly prevalent atherosclerotic syndrome associated with significant morbidity and mortality. PAD is defined by atherosclerotic obstruction of the arteries to the legs that reduce arterial flow during exercise or at rest, and is associated with systemic atherosclerosis. The clinical presentation of PAD is quite varied, including patients with atypical leg symptoms, classic intermittent claudication, and critical limb ischemia. Clinical assessment of these patients includes a comprehensive history, physical examination, and noninvasive and invasive vascular studies. The major risk factors for PAD include diabetes mellitus, tobacco abuse, hyperlipidemia, hypertension, and advanced age. Because of the presence of these risk factors, the systemic nature of atherosclerosis, and the high risk of ischemic events, patients with PAD should be candidates for comprehensive secondary prevention strategies, including aggressive glycemic control, all attempts at tobacco cessation, lipid lowering and antihypertensive treatment, antiplatelet therapy, and thorough foot care. This article reviews the comprehensive diagnostic algorithm and medical treatment strategies for patients with infrainguinal PAD.