Thyroglobulin measurements in tissue and serum play an integral role in the evaluation of patients who have thyroid cancer. Immunohistochemical detection of thyroglobulin in surgical specimens is useful in the differential diagnosis of tumors of unknown origin; however, the most important application of thyroglobulin measurement in clinical practice is in the postsurgical management of differentiated thyroid cancer. Serum thyroglobulin is a highly specific and sensitive tumor marker for detecting persistent or recurrent thyroid cancer and for monitoring clinical status. The reappearance of circulating thyroglobulin after total thyroid ablation is pathognomonic for the presence of tumor. The measurement of thyroglobulin in serum is challenging, however, and several analytical problems limit assay performance. Thyroglobulin autoantibody interference is a particularly significant concern that requires all thyroglobulin samples to be screened for their presence. No immunoassay is totally free from interference by thyroglobulin autoantibodies. Measurement of thyroglobulin mRNA to detect circulating tumor cells may help to overcome some of the limitations of current protein-detection methods; serum thyroglobulin will continue to remain the "gold standard." The complex functional features of thyroid carcinomas make sole reliance upon any one diagnostic technique, including thyroglobulin assessments, potentially misleading. Thyroglobulin measurements are a critical component of a multifaceted diagnostic approach to this disease.