Constitutional mutations of the RET proto-oncogene have been identified in multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) families. We sequenced RET exons 10 and 11 in 86 unrelated patients with an inherited predisposition to MTC (excluding MEN 2B). Germ-line mutations were Identified in 93% of the MEN 2A families and 67% of the FMTC families tested. All were missense mutations affecting one of three cysteines in the extracellular domain of the RET tyrosine kinase receptor. The prevalence of phaeochromocytoma and hyperparathyroidism was significantly higher in families with a mutation of cysteine 634. These data confirm the preferential localisation of MEN 2A and FMTC associated mutations and the strong correlation between clinical manifestations and the position of RET mutation. Although direst sequencing of RET exons 10 and 11 allows the identification of a constitutional mutation in a large proportion of MEN 2A and FMTC families, our data sustain the existence of other MTC predisposing mutations elsewhere in RET coding or regulating region.