Due to ageing populations and improvements in survival, increasing numbers of patients suffering from ischemic cardiovascular disease are not amenable to revascularization. Hence, interests are currently focused on "therapeutic angiogenesis", which is the clinical use of growth factors to enhance or promote the development of collateral blood vessels in ischemic tissue. Several growth factors (or genes encoding these growth factors) are now available for therapeutic vascular growth in normal and ischemic tissues. However, the successes of angiogenic therapy observed in pre-clinical studies have not been realized in clinical trials. Most animal studies demonstrating the physiologic effectiveness of angiogenic therapies have been performed in normal young animals, while clinical trials typically enroll older patients with various endothelial disruptive risk factors. The promising results of trials using endothelial function-improving strategies support the hypothesis that the decreased effectiveness of growth factor therapy due to endothelial dysfunction could be a principle reason for failure of trials using growth factors. We will have a retrospection of therapeutic angiogenesis trials and discuss the mechanisms that contribute to an impaired angiogenic response in the setting of endothelial dysfunction. We also briefly explore endothelial function-improving procedures that have the potentially therapeutic benefit of enhancing the angiogenic response.