Despite the availability of state-of-the-art treatment, there are still a significant number of patients with severe and diffuse atherosclerotic-obstructive coronary artery disease who are not only unsuitable for treatment of coronary artery disease, but also poor responders to medications. Additionally, atherosclerotic peripheral artery occlusive disease (PAOD) that affects 8-12% of Americans >65 years of age is associated with a major decline in functional status, increased myocardial infarction, and stroke rates as well as increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. Cell therapy has appeared as a potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function as well as for PAOD. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results, that is, with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These issues raise the need for developing an alternative strategic management with safety and efficacy for those of cardiovascular disease patients who are refractory to conventional therapy. Growing data have demonstrated that low energy of extracorporeal shockwave therapy (ESWT) dramatically improved chronic ischemic heart disease and hind limb ischemia, and preserving neurological function after ischemic stroke mainly through enhancing angiogenesis, upregulating the expression of stromal cell-derived factor-1α, recruiting endothelial progenitor cells/mesenchymal stem cells, as well as suppressing inflammation, generation of oxidative stress and cell apoptosis. Accordingly, this book chapter reviews the current data, that is, experimental studies and clinical trials focusing on the safety and efficacy as well as the underlying mechanisms of ESWT on improving ischemia-related organ dysfunction.