Critical limb ischemia (CLI) represents the most advanced clinical stage of peripheral arterial disease. It is usually caused by obstructive atherosclerotic arterial disease and is associated with very high morbidity and mortality. The pathophysiology of CLI is a complex and chronic process affecting the macrovascular and microvascular circulation of the muscle and non-muscle tissues of the lower limbs. In particular, the atherosclerosis-related vascular remodelling, angiogenesis and arteriogenesis are central phenomena in the process. The most common clinical manifestations of CLI are limb pain at rest, with or without trophic skin changes or tissue loss. Diagnosis of CLI is based on physical examination, ankle-brachial index measurement, duplex-ultrasound and angiography; transcutaneous oxygen may also help. Risk factor control is recommended for all patients with CLI. Individuals with minimal or no skin breakdown or in whom comorbid conditions avoid revascularization can be treated with medical therapy (antiplatelet agents, intravenous prostanoids, rheologic agents). Treatment of infection is mandatory to decrease the metabolic demands that hamper wound healing. Therapeutic angiogenesis has been pursued with several approaches ranging from gene therapy to the use of bone marrow-derived progenitor cells, but further phase II and III trials are needed. Finally, the evaluation of the risk, benefit and optimal timing of revascularization lesions or the decision about amputation and its extension is a complex decision that requires a multidisciplinary approach.