Peripheral artery disease (PAD) is the clinical manifestation of atherosclerosis that primarily affects peripheral arteries within the lower extremities. In this brief review, we describe the epidemiology and burden of disease of PAD within the United States, particularly among high-risk populations. Although the prevalence of PAD continues to increase and is typically higher among the elderly as well as men, women in lower socioeconomic strata are affected at rates two times that of men. Among racial/ethnic groups, Black and African-American patients both experience higher rates of disease as well as lower rates of access to preventative care. Moreover, despite an overall decrease in amputation rates among all patients with PAD, high-risk populations remain disproportionally affected. Specifically, patients in rural areas, African-American and Native-American patients, and those of low socioeconomic status carry the highest risk of amputation. Efforts to improve care among PAD patients should target these high-risk populations and offer comprehensive, evidence-based preventative care. Wide adoption and integration of these practices into comprehensive care models may help to mitigate amputation in the highest-risk populations. As our treatment pathways continue to evolve, we must place further emphasis on patient input and quality of life as we work toward continual improvement in the care of patients with PAD.