Severe limb ischemia represents a critical condition, being associated with high morbidity and mortality rates. Patients with critical limb ischemia (CLI) require urgent initiation of interventional or surgical treatment, as restoration of the blood flow is the only way to ensure limb salvage in these critical cases. At the same time, in acute limb ischemia, a dramatic form of sudden arterial occlusion of the lower limbs, the integrity of the limb is also seriously threatened in the absence of urgent revascularization. From patients with CLI, 40% are “no option CLI”, meaning patients in whom, due to anatomical considerations or to the severity of the lesions, there is no possibility to perform interventional or surgical treatment or they have failed. Therapeutic angiogenesis has been proposed to serve as an effective and promising alternative therapy for patients with severe limb ischemia who do not have any other option for revascularization. This review aims to present the current status in therapeutic angiogenesis and the role of different approaches (gene or cell therapy, intra-arterial vs. intramuscular injections, different sources of cells) in increasing the rates of limb salvage in patients with severe ischemia of the lower limbs.