Atherosclerosis is a systemic disease that affects all vascular beds, including coronary, cerebral, and peripheral arteries. With an estimated 236.6 million people living with peripheral artery disease (PAD), its prevalence ranks only behind coronary artery disease (CAD) and ischemic stroke in atherosclerotic diseases (Song et al., Lancet Glob Health 7(8):e1020–e1030, 2019). PAD is a common, underrecognized, and debilitating atherosclerotic disease of the lower extremities. Recognition and treatment of PAD remain relatively poor, in part due to the absence or subtlety of symptoms of early disease. Advanced PAD can manifest as a severely morbid condition resulting in progressive loss of function, as well as rest pain from claudication, gangrene, and limb amputation. Ischemic heart disease and stroke remain the leading causes of death globally and were responsible for 27% of all deaths in 2019 (The top 10 causes of death. World Health Organization, Geneva, 2020). Remarkably, however, the risk of an atherosclerotic cardiovascular disease (ASCVD) event is only modestly lower in patients with PAD compared to patients with CAD or prior stroke, and patients with PAD have an even higher risk of all-cause mortality (Colantonio et al., J Am Coll Cardiol 76(3):251–264, 2020). Our understanding of atherosclerosis has significantly advanced from earlier theories. In 1858, Virchow proposed that atherosclerosis was due to arterial injury propagating a maladaptive inflammatory and cellular process to generate atherosclerotic plaques (Basatemur et al., Nat Rev Cardiol 16(12):727–744, 2019). Work in the early 1900s by Ignatowski and Anichkov demonstrated that cholesterol was a critical mediator of atherosclerosis and recognized that lipid-rich diets increase the burden of atherosclerosis (Konstantinov and Jankovic, Tex Heart Inst J 40(3):247–249, 2013; Konstantinov et al., Tex Heart Inst J 33(4):417–423, 2006). Ross spearheaded the “response-to-injury” hypothesis in the 1970s, which further developed Virchow’s vascular injury theory to include platelet-derived factors, smooth muscle proliferation, and extracellular matrix deposition (Ross et al., Am J Pathol 86(3):675–684, 1977). Two decades later, the “response-to-retention” hypothesis proposed that atherogenic lipids are retained in arterial walls and induce an inflammatory cascade (Williams and Tabas, Arterioscler Thromb Vasc Biol 15(5):551–562, 1995; Ross, N Engl J Med 340(2):115–126, 1999). Since then, remarkable advances in scientific capabilities have greatly expanded our understanding of atherogenesis. The pathogenesis of PAD likely shares many common features of atherosclerosis in the coronary and cerebral arteries. Yet, the phenotype of PAD is unique, notable for intimal thickening with a paucity of inflammatory cells, a high prevalence of vascular calcification, and evidence that severe PAD that manifests as critical limb ischemia is at least in part a thromboembolic disease. This chapter will describe PAD, including its risk factors and epidemiology, normal and abnormal vascular function, pathogenesis of atherosclerosis, and the unique phenotype of PAD.