Lower extremity arterial disease (LEAD) affects over 200 million people worldwide but, as of today, is not adequately treated and represents an important cause of morbidity, mortality and disability. Although the use of antithrombotic therapy is recommended to prevent cardiovascular adverse events, patients with LEAD often receive inadequate prescription for antithrombotic agents (antiplatelets and anticoagulants). Historically, the inadequate use of antithrombotic drugs in this clinical setting has been ascribed to the lack of high quality scientific data obtained from clinical trials enrolling patients with LEAD. However, the results of more recent clinical trials support the use of antithrombotic drugs for these patients. The aim of this article is to summarize the available evidence supporting the prescription of antithrombotic agents in patients with LEAD.