Peripheral artery disease (PAD) of the lower extremities is a common manifestation of atherosclerosis that is increasing in global prevalence and in the associated public health costs. Ageing of the general population, combined with the pandemics of diabetes mellitus, metabolic syndrome, and tobacco use, is a major underlying factor. A broad range of care providers are involved in the management of patients with PAD, and all health-care professionals require familiarity with the risk factors, diagnosis, and treatment options for this common disease. Although medical therapies are the cornerstone of secondary prevention in atherosclerotic disease, they have limited direct limb-related benefits in advanced PAD. Despite a major evolution in technologies for limb revascularization, the increasing array of treatment options has not been accompanied by adequate evidence of their comparative effectiveness, which is needed to guide treatment decisions. This Review provides a framework for examining the current status of interventions for PAD, including an overview of disease staging, treatment goals, and the key factors associated with outcomes in defined subgroups. The status of evolving approaches to PAD, such as cell-based and gene-based therapies, and persistent unmet therapeutic needs in this field are also discussed.