The functioning of enteric neuronal circuitries has been elucidated in the recent past. Evidence is now gathering to explain how dysfunction of the enteric nervous system (ENS) may lead to human gastrointestinal motor disorders. These conditions include achalasia, congenital hypertrophic pyloric stenosis, chronic intestinal pseudo-obstruction, Hirschsprung's disease, chronic idiopathic constipation, and probably irritable bowel syndrome. Degenerative, inflammatory and genetic mechanisms exert a critical role in ENS dysfunction underlying gut dysmotility. The study of the ENS abnormalities in gut dysmotility provides a framework to better understand the mechanisms involved in degeneration and neuronal loss and fosters the development of targeted therapeutic options.