The endothelin (ET) family of proteins, which includes ET-1 (endothelin-1), ET-2 (endothelin-2) and ET-3 (endothelin-3), are vasoactive peptides that are involved in various functions throughout the body. Endothelins can affect the central nervous system and neuronal excitability, and they elicit potent vasoconstrictor action. While ET-1 is a potent, 21-amino acid vasoconstrictor peptide, ET-2 has the most potent vasoconstrictor activity. ET-3 functions as a ligand for endothelin receptor type B (ETBR) and, through this interaction, mediates the maturation of enteric neurons and melanocytes. Although ET-3 is expressed as a 238 amino acid peptide, it is post-translationally modified to produce a short active isoform and a long inactive isoform. Defects in the gene encoding ET-3 are the cause of a variety of disorders, including Hirschsprung disease type 1 (HSCR1), congenital central hypoventilation syndrome (CCHS) and Waardenburg syndrome type IV (WS4).