Atherosclerotic critical limb ischemia (CLI) is manifested by ischemic rest pain, non-healing ulcers or gangrene. The incidence of CLI is estimated to be approximately 500-1000 new cases per year per million people and is expected to grow in developed countries as the population ages with an increasing prevalence of diabetes. Patients diagnosed with CLI are at very high risk of major amputation and cardiovascular morbidity and mortality and experience poor physical function and quality of life. The goals of treatment for CLI are relieving ischemic pain, healing ulcers, preventing limb loss, improving patient function and quality of life, and prolonging survival. Prompt surgical or endovascular revascularization is currently recommended for limb salvage in CLI. All patients with CLI should receive cardiovascular risk reduction therapies, focused on optimizing antiplatelet therapy and risk factor management, to reduce cardiovascular event rates. Adjunctive pharmacotherapy with antithrombotic drugs, statins, and beta-blockers is critical to decrease perioperative cardiovascular complications in patients undergoing surgical vascular reconstruction and enhance postrevascularization arterial and graft patency. In non-reconstructable patients with stable pain and tissue loss, evidence suggests that prostanoids, dedicated wound care programs, and several mechanical devices, such as spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen therapy, can alleviate ischemic symptoms and improve limb salvage. Current medical armamentarium used in treating ischemic wounds also includes ultrasound and negative pressure wound therapy. Therapeutic neovascularization, including gene- and cell-based approaches, is a novel promising tool in the management of CLI under ongoing investigation.