Guideline-directed pharmacological therapy is highly underutilized in this population. Current guidelines recommend a multimodal approach to the treatment of peripheral artery disease (PAD), targeting broad risk factors for major cardiovascular events and adverse limb-related outcomes. This includes the initiation of antiplatelets and/or anticoagulants, statins, antihypertensives, diabetes agents, and medications to reduce claudication symptoms. Although there is substantial data supporting the use of pharmacologic therapies in this high-risk population, there are still critical evidence gaps that must be addressed. This includes better elucidating the benefits of medical therapies among patients with asymptomatic PAD, determining the optimal antiplatelet and anticoagulant regimens for patients who have undergone revascularization, and developing effective novel therapies to improve functional status.