Since the first demonstration by Van Herle et al. that thyroglobuling (Tg), the main iodo-protein of the thyroid gland, was detectable in the circulation of normal subjects by using specific radioimmunoassay, an impressive amount of papers has been produced, describing several clinical applications of Tg measurements. Now, measurement of Tg is the mainstay in the post-surgical follow-up of differentiated thyroid cancer and an integral part in the diagnostic evaluation of patients with benign thyroid diseases. In this article we will review the most relevant clinical application of Tg measurements in the blood and in other biological material, including: a) serum Tg in perinatal age and congenital hypothyroidism; b) serum Tg measurements in thyrotoxicosis factitia and in other thyrotoxic conditions associated with low iodine uptake; c) differential diagnosis of thyroid and parathyroid cysts; and d) clinical relevance of Tg measurement in thyroid cancer.