Critical limb ischemia (CLI) is a severe disease associated with a high risk of amputation and mortality. In patients who cannot be revascularized, several medical options have been tested, including the use of prostanoids, spinal cord stimulation, and lumbar sympathectomy. None of these treatments has demonstrated a benefit on the amputation rates after 6 months of follow-up; these treatments cannot therefore be recommended for CLI treatment in patients for whom surgery is not an option. In this setting, gene therapy and cell therapy to stimulate angiogenesis have been tested mainly in phase I and II clinical trials and are reviewed in this article. These studies demonstrated the short-term safety and feasibility of these new approaches, but larger randomized studies remain necessary to demonstrate their clinical benefits and longterm safety.