Multiple endocrine neoplasia Type 2 (MEN 2) is an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC). The disease has three subtypes, which are distinguished by the presence of additional phenotypes. In particular, pheochromocytoma occurs in approximately 50% of patients with the MEN 2A or MEN 2B subtypes, but is not found in patients with the milder disease subtype, familial MTC (FMTC). All subtypes of MEN 2 are caused by activating mutations of the RET (REarranged in Transfection) proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase, required for development of neuroendocrine cell types and the kidneys. All MEN 2 subtypes are associated with single amino acid substitution mutations that are found in either the extracellular domain or in the kinase domain of RET. There are strong genotype-phenotype correlations in MEN 2 between patient phenotype and the specific residue that is mutated. MEN 2A is primarily associated with substitutions at five extracellular cysteine residues, while 95% of MEN 2B is associated with a single methionine to threonine mutation in the kinase domain (M918T). In FMTC, RET mutations are more broadly distributed, with both extracellular cysteines and intracellular sites implicated. In all cases, MEN 2-RET mutations result in constitutive activation of the receptor, although the mechanism and relative functional effects of the mutations vary. Recent advances in functional characterization and development of molecular models of RET and of various MEN 2-RET mutants are helping us understand tissue-specific differences in oncogenic potential conferred by the different RET mutations. Here, we discuss and compare several well-characterized mutations of the extracellular and kinase domains, which have quite varied functional implications.