Synthesis of tri-iodothyronine (T(3)) and thyroxine (T(4)) follows a metabolic pathway that depends on the integrity of the thyroglobulin structure. This large glycoprotein is a homodimer of 660 kDa synthesized and secreted by the thyroid cells into the lumen of thyroid follicle. In humans it is coded by a single copy gene, 270 kb long, that maps on chromosome 8q24 and contains an 8.5 kb coding sequence divided into 48 exons. The preprotein monomer is composed of a 19-amino acid signal peptide followed by a 2749-amino acid polypeptide. In the last decade, several mutations in the thyroglobulin gene were reported. In animals, four of them have been observed in Afrikander cattle (p.R697X), Dutch goats (p.Y296X), cog/cog mouse (p.L2263P) and rdw rats (p.G2300R). Mutations in the human thyroglobulin gene are associated with congenital goiter or endemic and nonendemic simple goiter. Thirty-five inactivating mutations have been identified and characterized in the human thyroglobulin gene: 20 missense mutations (p.C175G, p.Q310P, p.Q851H, p.S971I, p.R989C, p.P993L, p.C1058R, p.C1245R, p.S1447N, p.C1588F, p.C1878Y, p.I1912V, p.C1977S, p.C1987Y, p.C2135Y, p.R2223H, p.G2300D, p.R2317Q, p.G2355V, p.G2356R), 8 splice site mutations (g.IVS3-3C>G, g.IVS5+1G>A, g.IVS10-1G>A, g.IVS24+1G>C, g.IVS30+1G>T, g.IVS30+1G>A, g.IVS34-1G>C, g.IVS45+2T>A) 5 nonsense mutations (p.R277X, p.Q692X, p.W1418X, p.R1511X, p.Q2638X) and 2 single nucleotide deletions (p.G362fsX382, p.D1494fsX1547). The thyroglobulin gene has been also identified as the major susceptibility gene for familial autoimmune thyroid diseases (AITD) by linkage analysis using highly informative polymorphic markers. In conclusion the identification of mutations in the thyrogobulin gene has provided important insights into structure-function relationships.