The GDNF family of neurotrophic factors forms a subfamily within the TGF-β superfamily. These proteins are potent survival factors for various central and peripheral neurons during development and the adult animal. The GDNF family members (GDNF, neurturin, artemin and persephin) signal through multicomponent receptors that consist of the Ret receptor tyrosine kinase and one of four glycosyl-phosphatidylinositol (GPI)-linked ligand-binding subunits (GFRα-1 -4). GFRα-1 -2, -3 and -4 are the preferred ligand-binding subunits for GDNF, neurturin, artemin and persephin, respectively. The Ret tyrosine-kinase receptor is encoded by the c-ret proto-oncogene. Mutations of the ret gene have been associated with various human diseases affecting tissues derived from the neural crest, including Hirschsprung’s disease, multiple endocrine neoplasia MEN2A and MEN2B, and familial medullary thyroid carcinoma. Human and mouse Ret share 83% amino acid sequence homology (77% homology in the extracellular domain and 93% homology in the cytoplasmic domain). Although Ret does not bind GDNF ligands directly, the extracellular domain of Ret binds the GDNF-GFR-α complex with high affinity and is a potent GDNF antagonist in the presence of soluble GFR-α.