Each year, more than 18 million adults in the United States receive manual therapies, at a total annual out-of-pocket cost of $3.9 billion. Although there is growing evidence supporting the efficacy of manual therapies, little is known about the mechanisms underlying these treatments. This lack of basic knowledge significantly limits the development of rational strategies for the use of these treatments and potentially hinders their acceptance by the wider scientific and health care communities. Many authors have hypothesized that manual therapies act by disrupting the pain-spasm-pain cycle, but relatively little experimental evidence has supported this hypothesis. The authors have tested this hypothesis and summarize their work on the biology of manual therapies.