The rearranged during transfection (RET) proto-oncogene was identified in 1985 and, very soon thereafter, a rearrangement named RET/PTC was discovered in papillary thyroid carcinoma (PTC). After this discovery, other RET rearrangements were found in PTCs, particularly in those induced by radiation. For many years, it was thought that these genetic alterations only occurred in PTC, but, in the past couple of years, some RET/PTC rearrangements have been found in other human tumours. 5 years after the discovery of RET/PTC rearrangements in PTC, activating point mutations in the RET proto-oncogene were discovered in both hereditary and sporadic forms of medullary thyroid carcinoma (MTC). In contrast to the alterations found in PTC, the activation of RET in MTC is mainly due to activating point mutations. Interestingly, in the past year, RET rearrangements that were different to those described in PTC were observed in sporadic MTC. The identification of RET mutations is relevant to the early diagnosis of hereditary MTC and the prognosis of sporadic MTC. The diagnostic and prognostic role of the RET/PTC rearrangements in PTC is less relevant but still important in patient management, particularly for deciding if a targeted therapy should be initiated. In this Review, we discuss the pathogenic, diagnostic and prognostic roles of the RET proto-oncogene in both PTC and MTC.