One of the main goals in the treatment of myocardial ischemia is the development of effective therapy for angiogenesis and neovascularization. The first evidence demonstrating alleviation of myocardial ischemia and increased number of collateral blood vessels was reported in the early 90s following intra-coronary administration of basic fibroblast growth factor protein in canine. This study established the ground for extensive investigations to demonstrate the use of other angiogenic growth factor proteins, genes administered directly or incorporated in viruses, and more recently, endothelial progenitor stem cells (embryonic and adults). The positive results observed in animals failed, in most cases, to repeat themselves in clinical-trials in human patients. Therefore, additional experiments are warranted to allow full understanding of the mechanism underlying new blood vessel formation before further clinical studies are undertaken. This review will explore the milestones of angiogenic investigations and their clinical application.