A series of gene targeting research have revealed novel roles of endothelins (ETs), peptides with potent vasoconstrictive and proliferative activities, in neural crest development in mammals. The phenotype of mice lacking the ET-1/ET-A receptor-mediated signalling affects cranial/cardiac neural crest-derived structures including the branchial arches and great vessels, and is highly similar to a set of the phenotypes of the avian neural crest ablation model. In contrast, mice lacking the ET-3/ET-B receptor-mediated signalling have defects in enteric neurons and melanocytes derived from trunk/vagal neural crest, resulting in megacolon and coat color spotting. Thus, both distinct pathways of the ET system seem to participate in the normal development of different neural crest lineages. Moreover, mutations in the human ET-3 and ET-B receptor genes have been identified in patients with Hirschsprung disease. As for the mechanisms involving the ET system in neural crest development, HANDs and Goosecoid, transcriptional factors essential for embryogenesis, have been suggested as key molecules downstream to the ET-mediated signalling in cranial/cardiac neural crest.