Research in animal models of ischemia has shown that administration of angiogenic growth factors, either as a recombinant protein or by gene transfer, can augment nutrient perfusion through neovascularization to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries; a strategy termed "therapeutic angiogenesis." In animal models and clinical trials, the best studied cytokines with angiogenic activity are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Clinical trials of therapeutic angiogenesis in patients with critical limb ischemia demonstrated resolution of rest pain and/or improved limb integrity, increased pain-free walking time and ankle-brachial index, newly visible collateral vessels by digital subtraction angiography, and qualitative evidence of improved distal flow by magnetic resonance imaging. Initial clinical trials in patients with end-stage coronary artery disease using direct myocardial injection via thoracotomy resulted in large increases in exercise time and marked reductions in anginal symptoms, as well as objective evidence of improved perfusion and left ventricular function. Larger scale placebo-controlled trials have been limited to intracoronary and intravenous administration of recombinant protein, and have not shown significant improvement in exercise time or angina compared to placebo. Larger scale placebo-controlled studies of gene transfer using catheter-based endocardial delivery are in progress. Future clinical studies are required to determine the optimal dose, formulation, route of administration, and combinations of growth factors, as well as the requirement for endothelial progenitor cell or stem cell supplementation, to provide effective and safe therapeutic angiogenesis for patients with critical limb ischemia and chronic myocardial ischemia who are not candidates for conventional revascularization procedures.