The RET (“rearranged during transfection”) proto-oncogene encodes a receptor-type tyrosine kinase with an intracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. The ligands for RET have been identified as neurotrophic factors of the glial cell-line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin, and persephin. All these factors activate RET via different glycosyl phosphatidylinositol-linked GFRa receptors. The receptor appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the autonomic nervous system. The RET protein is also necessary for normal kidney development and the production of sperm (spermatogenesis). Mutations in the RET gene have been found in a number of human diseases, including several different cancers of neuroendocrine origin and a gut syndrome characterized by intestinal obstruction known as Hirschsprung’s disease.