Patients with critical limb ischemia (CLI) without potential for revascularization are currently without alternate therapies. Several gene therapy trials have tested angiogenesis factors, hepatic growth factor, vascular endothelial growth factor, and basic fibroblast growth factor, in rescuing CLI patients from amputation and mortality, and for improved quality of life including decreased pain, improved healing, and blood flow. Trial results have been variable, with HGF gene therapy being the most successful. New studies examining each of these angiogenic factors provide insights that will be useful for the design of effective therapeutic strategies. © 2012 Elsevier Inc.