The study of vertebrate pigmentary anomalies has greatly improved our 
understanding of melanocyte biology. One such disorder, Waardenburg syndrome 
(WS), is a mendelian trait characterized by hypopigmentation and sensorineural 
deafness. It is commonly subdivided into four types (WS1-4), defined by the 
presence or absence of additional symptoms. WS type 4 (WS4), or Shah-Waardenburg 
syndrome, is also known as Hirschsprung disease Type II (HSCR II) and is 
characterized by an absence of epidermal melanocytes and enteric ganglia. 
Mutations in the genes encoding the endothelin type-B receptor (EDNRB) and its 
physiological ligand endothelin 3 (EDN3) are now known to account for the 
majority of HSCR II patients. Null mutations in the mouse genes Ednrb and Edn3 
have identified a key role for this pathway in the normal development of 
melanocytes and other neural crest-derived lineages. The pleiotropic effects of 
genes in this pathway, on melanocyte and enteric neuron development, have been 
clarified by the embryologic identification of their common neural crest (NC) 
ancestry. EDNRB and EDN3 are transiently expressed in crest-derived melanoblast 
and neuroblast precursors, and in the surrounding mesenchymal cells, 
respectively. The influence of EDNRB-mediated signaling on the emigration, 
migration, proliferation, and differentiation of melanocyte and enteric neuron 
precursors, in vivo and in vitro has recently been the subject of great 
scrutiny. A major emergent theme is that EDN3-induced signaling prevents the 
premature differentiation of melanocyte and enteric nervous system precursors 
and is essential between 10 and 12.5 days post-coitum. We review the present 
understanding of pigment cell development in the context of EDNRB/EDN3--a 
receptor-mediated pathway with pleiotropic effects.