Despite the excellent prognosis, differentiated thyroid carcinoma (DTC) may recur in 20-40%, and prognosis is particularly related to early detection of recurrent disease. Therefore, long-term follow-up with sensitive tests is need. Serum thyroglobulin (Tg) has an established role as a tumor marker of relapse. However, there are technical limitations of Tg immunoassays, in special, the interference of anti-Tg antibodies and the method sensitivity is dependent on TSH stimulation. Detection of circulating malignant cells by amplification of tumor-specific mRNA showed initial promising results. However, almost one decade of studies of Tg mRNA detection in peripheral blood, its real contribution for DTC follow-up had not yet been established. After a critical analysis of published data, it is clear that there are many protocol differences and conflicting results. Therefore, it seems that amplification of thyroid-specific mRNAs is not superior to sensitive Tg assays and illegitimate transcription and alternative splicing of Tg are factors that may influence mRNA test specificity.