Peripheral arterial disease is a growing global burden, with chronic limb-threatening ischemia (CLTI), its most advanced stage, associated with high morbidity, mortality, and economic costs. While randomized controlled trials are the gold standard for evaluating treatment strategies, their external validity is often limited by strict inclusion criteria that exclude complex, real-world patients with CLTI. This review underscores the need for evidence-based pathways tailored to real-world CLTI populations.