In patients in whom antianginal medications fail to provide sufficient symptomatic relief, additional interventions such as angioplasty or bypass surgery may be required. Although both types of intervention have been shown to be effective for various types of patients, a certain group of patients may not be candidates for either intervention because of the diffuse nature of their coronary artery disease. Moreover, there are many patients in whom recurrent narrowing and/or occlusion of bypass conduits after initially successful surgery has left the patient again symptomatic with no further angioplasty or surgical option. Ischemic muscle represents a promising target for gene therapy with naked plasmid DNA. Intramuscular transfection of genes encoding angiogenic cytokines, particularly those naturally secreted by intact cells, may constitute an alternative treatment strategy for patients with extensive tissue ischemia in whom contemporary therapies (antianginal medications, angioplasty, bypass surgery) have previously failed or are not feasible. This strategy is designed to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed “therapeutic angiogenesis.” Preclinical animal studies from our laboratory have established that intramuscular gene transfer may be used to successfully accomplish therapeutic angiogenesis. More recently, phase 1 clinical studies from our institution have established that intramuscular gene transfer may be used to safely and successfully accomplish therapeutic angiogenesis in patients with critical limb ischemia. The notion that this concept could be extrapolated to the treatment of chronic myocardial ischemia was demonstrated in our laboratory by administering recombinant human vascular endothelial growth factor (VEGF) to a porcine model of chronic myocardial ischemia. Recent experiments performed in this same porcine model of myocardial ischemia have shown that direct intramyocardial gene transfer of naked plasmid DNA encoding VEGF (phVEGF₁₆₅, the identical plasmid used in our previous animal and human clinical trials) can be safely and successfully achieved through a minimally invasive chest wall incision. Finally, initial results have supported the concept that intramyocardial injection of naked plasmid DNA encoding VEGF can achieve therapeutic angiogenesis, as demonstrated by clinical improvement in patient symptoms and improved myocardial perfusion shown by single-photon emission computed tomography–sestamibi imaging. (Am Heart J 1999;138:S132-S141.)