Despite advances in surgical and percutaneous revascularization techniques, nearly one-third of patients with ischemic coronary artery disease are not candidates for revascularization due to suboptimal anatomy or receive suboptimal revascularization from these standard procedures. Neovascularization of the myocardium is not only a physiologic response to ischemia, but also potentially the target of new therapeutic strategies. Induced angiogenesis via protein, gene, and cell-based therapies showed initial promise in experiments using otherwise healthy laboratory animals. However, failure to translate these gains into humans prompted further study into the vascular environment and endothelial dysfunction. Understanding that factors such as hypertension, diabetes, and hyperlipidemia are not only placing patients at risk for coronary artery disease but also undermining our attempts in neovascularization therapies, has prompted us to rethink our therapeutic approach. Future directions for therapeutic neovascularization lie in therapies combining optimization of the vascular environment, improvement of endothelial function and other aspects of vascular formation and development.