Cigarette smoking is one of the most important risk factors for peripheral arterial disease (PAD). Smoking increases the risk of PAD by several fold and is a more influential risk factor for PAD than for coronary artery disease. Multiple pathophysiologic mechanisms may account for the prevalence of atherosclerosis in cigarette smokers. These include abnormalities of endothelial function, lipoprotein metabolism, coagulation, and platelet function. Smoking cessation decreases the risk of cardiovascular morbidity and mortality, and may improve functional capacity in patients with PAD. Therapies to promote smoking cessation include counseling, nicotine replacement, and bupropion. Healthcare providers must enhance their efforts and target smoking cessation as a modifiable risk factor in patients with PAD and other manifestations of atherosclerosis.