Thyroglobulin (Tg), a large glycoprotein molecular synthesized and secreted by thyroid follicular cells, serves as a substrate for the synthesis of thyroid hormones. Tg can also be produced with varying levels by differentiated thyroid carcinoma (DTC) originating from thyroid follicular cells. As a specific tumor marker for DTC, Tg has been used in DTC patients for post-surgical risk stratification, efficacy evaluation, long-term follow-up surveillance and prognostic estimation. There are many practical issues in using serum Tg value to assess DTC disease, because of its heterogeneous molecular structure and the technical restriction in its blood value detection as well as the interference of Tg autoantibodies. Even so, the ultrasensitive detection methods developed in recent years further increased the clinical applicability of Tg. Here, the authors provide a brief overview of the research progress of Tg and some important points in its clinical applications.