The goals of this review are to summarize some of the novel observations on the genetic and molecular basis of enteric nervous system disorders, with particular emphasis on the relevance of these observations to the practicing neurogastroenterologist. In the last two decades, there has been a greater understanding of genetic loci involved in congenital forms of pseudo-obstruction and Hirschsprung's disease; and the contribution of endothelins and nuclear transcription factors to the development of the enteric nervous system. In addition, clarification of the molecules involved in the activation of the peristaltic reflex, the disorders of the interstitial cells of Cajal, the clinical manifestations of mitochondrial cytopathies affecting the gut, and the application of neurotrophic factors for disorders of colonic function have impacted on practical management of patients with gut dysmotility.