RET (proto-oncogene tyrosine-protein kinase receptor Ret) activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. Simple variants in RET are seen in about 3% of all tumors, including 25% of thyroid tumors. Germline RET variants are diagnostic for multiple endocrine neoplasia and familial medullary thyroid carcinoma. RET-activating mutations and rearrangements are common in medullary thyroid cancer. RET variants predict responses to kinase inhibitors.