1. The enteric nervous system (ENS) is derived from cells that migrate to the bowel from the neural crest. These émigrés must find the gut, reach their correct locations within its wall and finally differentiate as neurons or glia. 2. Because the crest-derived precursor population is multipotent when it colonizes the bowel, the enteric micro-environment plays a prominent role in ENS development. 3. A number of molecules of the enteric micro-environment have been found to promote the development of neurons. 4. However, endothelin (ET)-3 appears to be different from any of these in that its role appears to be to prevent premature neuronal differentiation. 5. By activating ETB receptors, ET-3 inhibits the differentiation of crest-derived cells into neurons and promotes the development of smooth muscle. 6. The effect of ET-3 on smooth muscle down-regulates the secretion of laminin-1, which is a promoter of the formation of neurons. 7. In the absence of ET-3/ETB, crest-derived cells develop as neurons and, thus, cease migrating before they complete the colonization of the bowel. This premature development leaves the terminal colon aganglionic.