Thyroglobulin (TG) is a normal constituent of serum detectable by radioimmunoassay in 75% to 90% of healthy adults. Levels are altered in a number of physiological and pathological conditions. Although the indications for serum TG measurements have not been clearly established, it is simple, inexpensive, and presents no risk of radiation exposure. Problems include variable sensitivity and reproducibility of assays, interference by TG autoantibodies, and changes induced by certain diagnostic or therapeutic interventions. Serum TG measurement is primarily used as a tumor marker in thyroid carcinoma. Values are almost invariably high with disseminated metastases. After total ablation of thyroid tissue, serum TG determination is useful in separating patients in remission from those with residual metastatic disease. Serial measurements in the same patients are useful in monitoring the effect of treatment of nonfunctioning thyroid metastases. It is of no proved value in the initial diagnosis of thyroid carcinoma. Controversy still exists regarding the advantages of measuring TG during hormonal therapy. The assay may aid in the diagnosis of thyrotoxicosis factitia, painless subacute thyroiditis, and neonatal hypothyroidism.