Ischemic heart disease is the leading cause of death and the number of refractory severe patients is increasing. Therefore, it is crucial to develop new therapeutic strategies for severe ischemic heart disease. We found that a low-energy shock wave (SW) (about 10% of energy density that used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Based on this in vitro study, we have started in vivo studies and have demonstrated that extracorporeal cardiac shock wave therapy with a low-energy SW upregulates the expression of VEGF, induces neovascularization, and improves myocardial ischemia in a porcine model of chronic myocardial ischemia without any adverse effects in vivo. On the basis of the promising results in animal studies, we have subsequently developed a new, non-invasive angiogenic therapy with low-energy SW for ischemic heart disease. Our extracorporeal cardiac SW therapy improved symptoms and myocardial perfusion evaluated with stress-scintigraphy in patients with severe coronary artery disease without indication of percutaneous coronary intervention or coronary bypass surgery. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective to ameliorate LV remodeling after acute myocardial infarction in pigs and to enhance angiogenesis in hindlimb ischemia in rabbits. Based on these animal studies, we are also conducting clinical studies in patients with acute myocardial infarction and those with peripheral artery disease. Thus, our extracorporeal cardiac SW therapy is an effective, safe, and non-invasive angiogenic strategy in cardiovascular medicine and its indication is now rapidly expanding.