Critical limb ischemia (CLI), the most advanced form of peripheral artery disease, is associated with significant morbidity, mortality, and health care resource utilization. It is also associated with physical, as well as psychosocial, consequences such as amputation and depression. Importantly, after a major amputation, patients are at heightened risk of amputation on the contralateral leg. However, despite the technological advances to manage CLI with minimally invasive technologies, this condition often remains untreated, with significant disparities in revascularization and amputation rates according to race, socioeconomic status, and geographic region. Care remains disparate across medical specialties in this rapidly evolving field. Many challenges persist, including appropriate reimbursement for treating complex patients with difficult anatomy. This paper provides a comprehensive summary that includes diagnostic assessment and analysis, endovascular versus open surgical treatment, regenerative and adjunctive therapies, and other important aspects of CLI.