The prevalence of peripheral artery disease is growing, with millions of people globally suffering its end-stage manifestation, chronic limb-threatening ischemia (CLTI). Revascularization procedures like lower extremity bypass play a vital role in limb salvage but optimal medical therapy is essential for maximizing the benefit of these procedures and reducing long-term risks of cardiovascular and limb-related events. Patients with PAD who undergo lower extremity bypass warrant a comprehensive approach to risk factor modification for both primary and secondary prevention of cardiovascular and limb-related complications. This includes appropriate use of high-intensity statins, smoking cessation, and management of hypertension and diabetes. Additionally, antiplatelet therapy is indicated for all patients with CLTI and additional treatment with low-dose anticoagulation may also be beneficial. Optimal medical therapy is essential for optimizing outcomes in patients with PAD undergoing lower extremity bypass.