Patients with critical limb ischemia (CLI) represent the highest risk patients with peripheral artery disease (PAD), with high rates of death, amputation, and other cardiovascular events. Previously, nonsurgical options for patients with CLI were limited. However, advances in endovascular techniques such as angiosome-based revascularization and technologies such as drug-eluting balloon and stent platforms have dramatically improved the therapeutic outlook. Additionally, advances in stem cell-based therapy and angiogenic factors show promise as adjuvant medical therapy.