Development of the ENS requires the function of a diverse set of genes encoding transcription factors, signaling molecules, and their receptors. Mutations of these genes result in altered ENS function in animals and humans. In particular, such mutations have been shown to contribute to many cases of Hirschsprung's disease. Elucidation of the mechanisms of ENS development and function allow the development of new approaches to the diagnosis, therapy, and prevention of human disorders of gastrointestinal motility.