Shock waves are high-energy acoustic waves generated under water with high voltage explosion and vaporization. Shock wave in urology (lithotripsy) is primarily used to disintegrate urolithiasis, whereas shock wave in orthopedics (orthotripsy) is not used to disintegrate tissues, rather to induce neovascularization, improve blood supply and tissue regeneration. The application of shock wave therapy in certain musculoskeletal disorders has been around for approximately 15 years, and the success rate in non-union of long bone fracture, calcifying tendonitis of the shoulder, lateral epicondylitis of the elbow and proximal plantar fasciitis ranged from 65% to 91%. The complications are low and negligible. Recently, shock wave therapy was extended to treat other conditions including avascular necrosis of femoral head, patellar tendonitis (jumper's knee), osteochondritis dessicans and non-calcifying tendonitis of the shoulder. Shock wave therapy is a novel therapeutic modality without the need of surgery and surgical risks as well as surgical pain. It is convenient and cost-effective. The exact mechanism of shock wave therapy remains unknown. Based on the results of animal studies in our laboratory, it appears that the mechanism of shock waves first stimulates the early expression of angiogenesis-related growth factors including eNOS (endothelial nitric oxide synthase), VEGF (vessel endothelial growth factor) and PCNA (proliferating cell nuclear antigen), then induces the ingrowth of neovascularization that improves blood supply and increases cell proliferation and eventual tissue regeneration to repair tendon or bone tissues. The rise of angiogenic markers occurred in as early as one week and only lasted for approximately 8 weeks, whereas the neovascularization was first noted in 4 weeks and persisted for 12 weeks or longer along with cell proliferation. These findings support the clinical observation that the effect of shock wave therapy appears to be dose-dependent and symptom improvement with time. Additional information including the cellular and molecular changes after shock wave therapy are needed for further clarification on the mechanism of shock wave therapy in musculoskeletal system.