The rearranged during transfection (RET) proto-oncogene encodes a transmembrane receptor tyrosine kinase and its alterations cause various cancers and developmental disorders. Gain-of-function mutations caused by gene rearrangements have been found in papillary thyroid carcinoma, non-small-cell lung carcinoma, and other cancers, while point mutations are responsible for hereditary cancer syndrome, multiple endocrine neoplasia type 2, and sporadic medullary thyroid carcinoma. Loss-of-function point mutations or deletions lead to Hirschsprung disease, a developmental disorder associated with aganglionosis of the intestinal tract. RET is also involved in various physiological and developmental functions through activation by glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs). Gene knockout studies have revealed that GDNF-RET signaling plays an essential role in the development of the enteric nervous system, kidney, and urinary tract, as well as in the self-renewal of spermatogonial stem cells. Moreover, recent progress in developing RET-selective inhibitors has significantly contributed to treating patients with RET-altered cancers. This chapter describes and discusses the functions associated with disease and physiology.