The population of patients with end-stage symptomatic coronary and peripheral vascular disease is ever-expanding. Many of these patients no longer have options for mechanical revascularization, and despite maximal medical therapy, they remain physically limited due to angina or critical limb ischemia. The fundamental problem in these patients is insufficient blood supply to muscle due to severely diseased conduit vessels to the target tissue. Therefore, it seems logical that increasing the blood supply to ischemic tissue will relieve symptoms. One potential means to achieving this goal is via therapeutic angiogenesis. The molecular mechanisms behind vascular development are being elucidated, and animal models have shown that mediators of vascular development can be harnessed to produce new capillaries in ischemic tissue. These mediators include cytokines such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Angiogenic cytokines can be delivered in several forms including recombinant protein or via gene delivery as a naked plasmid or via viral vector. This chapter will describe the clinical trial experience to date with delivery of non-viral gene therapy for therapeutic angiogenesis in humans with disabling myocardial ischemia and peripheral vascular disease.