Myocardial ischemia is one of the most promising targets of gene therapy. Although several growth factors and delivery approaches have yielded positive results in preclinical studies, first clinical studies have shown little or no real clinical benefit to the patients. It is likely that less than optimal gene therapy approaches have been used so far, and more thorough preclinical studies are needed in order to establish safe, efficient pro-angiogenic therapy. Growth factor, gene transfer vector, delivery method and target microenvironment need to be chosen based on the therapeutic target. It has become apparent that induction of large collateral arteries in the myocardium may need a different approach than rapid growth of neovasculature around infarction scar. Large animal models are necessary in the determination of optimal therapeutic agent, dose and clinically relevant delivery strategy.