Context: Peripheral arterial disease (PAD) affects approximately 20% of adults older than 55 years and is a powerful predictor of myocardial infarction, stroke, and death due to vascular causes. The goals of treatment are to prevent future major coronary and cerebrovascular events and improve leg symptoms. Objective: To review the best evidence for medical treatment of PAD. Evidence Acquisition: MEDLINE and the Cochrane database were searched from 1990 to November 2005 for randomized trials and meta-analyses of medical treatments for PAD. References from these articles were also searched. Search terms included, singly and in combination: peripheral arterial disease, peripheral artery disease, PAD, randomized controlled trial, controlled trial, randomized, and meta-analysis. Particular attention was directed toward randomized controlled trials and meta-analyses of clinically relevant medical treatments for PAD. Outcome measures included leg symptoms (intermittent claudication and walking distance), death, and major coronary and cerebrovascular events. Evidence Synthesis: Symptoms of leg claudication, walking distance, and quality of life can be improved by smoking cessation (physician advice, nicotine replacement therapy, and bupropion), a structured exercise program, statin drugs, cilostazol, and angiotensin-converting enzyme inhibitors. The risk of major coronary and cerebrovascular events can be reduced through lowering blood pressure with angiotensin-converting enzyme inhibitors and other antihypertensive drugs, use of statin drugs, antiplatelet therapy with aspirin or clopidogrel, and probably by stopping smoking. Conclusion: The substantial and increasing burden of PAD, and its local and systemic complications, can be reduced by lifestyle modification (smoking cessation, exercise) and medical therapies (nicotine replacement therapy, bupropion, antihypertensive drugs, statins, and antiplatelet drugs).