Thyroid nodules can be found in up to 50% of inhabitants of iodine-deficient areas and are classified as hot or cold thyroid nodules according to their scintigraphic characteristics. Studies of hot thyroid nodules with comparable mutation detection methods and screening at least exon 10 of the TSH receptor reported frequencies for somatic TSH-receptor mutations ranging from 20 to 82% in patients with similar iodine supply. We have recently screened 75 hot thyroid nodules for somatic TSH-receptor mutations with the more sensitive DGGE method and found somatic TSH-receptor mutations in 57% and Gsalpha mutations in 3%. As 50% of the mutation-negative nodules from female patients are of monoclonal origin when tested for X-chromosome inactivation somatic mutations in other genes are likely to cause the development of hot thyroid nodules. Scintigraphically nonsuppressible areas have been identified in up to 40% of euthyroid goiters in iodine-deficient areas. We recently identified somatic TSH-receptor mutations in microscopic autonomous areas with increased 125T uptake in euthyroid goiters studied by autoradiography 20 years ago. These constitutively activating somatic TSH-receptor mutations in minute autoradiographically hot areas of euthyroid goiters are very likely starting foci which most likely lead to toxic thyroid nodules in iodine-deficient goiters. Therefore iodine deficiency does not only lead to euthyroid goiters but also to thyroid autonomy. The latter is also suggested by epidemiologic studies. Similar mechanisms induced by iodine deficiency and the subsequent hyperplasia, mutagenesis, and selection of cell clones could also lead to cold thyroid nodules by somatic mutations that only initiate growth but not hyperfunction of the affected thyroid epithelial cell. Somatic ras mutations have frequently been detected in histologically characterized thyroid adenomas or adenomatous nodules. However, they seem to be rare in cold thyroid nodules. Since the majority of these latter nodules and 60% of the cold thyroid nodules are monoclonal other somatic mutations are likely in these nodules.