After extensive investigation in preclinical studies and recent clinical trials, gene therapy has been established as a potential method to induce therapeutic angiogenesis in ischemic myocardial and limb disease. Advancements in viral and nonviral vector technology including cell-based gene transfer will continue to improve transgene transmission and expression efficiency. An alternative strategy to the use of transgenes encoding angiogenic growth factors is therapy based on transcription factors such as hypoxia-inducible factor-1alpha (HIF-1alpha) that regulate the expression of multiple angiogenic genes. Further understanding of the underlying biology of neovascularization is needed to determine the ability of growth factors to induce functionally significant angiogenesis in patients with atherosclerotic disease and associated comorbid conditions including endothelial dysfunction, which may inhibit blood vessel growth. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. However, limited evidence of efficacy resulted from early phase II studies of angiogenic gene therapy for ischemic myocardial and limb disease. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled phase II and III clinical trials.