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Thyroglobulin (Tg) is a precursor for thyroid hormone, specifically synthesized by thyroid follicular cells upon stimulation by the thyroid stimulating hormone (TSH). Damage to the thyroid cells caused by benign or malignant thyroid diseases cause the release of Tg into circulation. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, which has an excellent prognosis if detected and treated early. This review describes the clinical and laboratory aspects of Tg and AntiTg measurement in the management of DTC. The serum Tg measurement has been used in the pre- and post-operative management of DTC. The clinical significance of Tg and the role its low level can play in the diagnosis and monitoring of DTC as well as in the prediction of its recurrence must be understood. DTC may lead to the production of a different Tg with novel immunogenic cancer epitopes that can induce TgAb synthesis. The preoperative TgAb level has shown a high predictive value for DTC, while postoperative serum TgAb can be used for the detection of disease persistence and recurrence. Despite the importance of TgAb level in DTC management, the presence of TgAb interferes with the analysis of Tg measurement, thus limiting its clinical utility. There is no established value regarding at which level TgAb interferes with Tg measurement. Available methods in measuring Tg and TgAb should emphasize the lower and upper limits of their detection, especially for postoperative monitoring and early disease recurrence detection. The accurate measurement of serum Tg and TgAb is pertinent to the follow-up of DTC patients, and any suspicious results must be interpreted in accordance with clinical findings in view of a present possible assay interference.