Differentiated thyroid carcinoma (DTC) is a slow-growing tumor that represents 1% of all malignant tumors and is the most frequent endocrine cancer. ¹⁸F-Fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) imaging is an increasingly important imaging tool in oncology and is still under investigation in numerous studies looking into its efficacy and cost-effectiveness. Despite the fact that ¹⁸F-FDG-PET/CT has been shown to be a powerful and accurate diagnostic tool in patients affected by DTC with high serum thyroglobulin (Tg) levels and negative radioiodine (¹³¹I) total body scan, its definitive role is not completely clear, in particular regarding the role of thyroid stimulating hormone (TSH) and Tg value "cutoff" over which is better to perform the study. In this review, these issues are analyzed to clarify controversial aspects and identify established cornerstones. In particular, the literature analysis suggests that levothyroxine withdrawal is preferable in cases of relatively low Tg levels (<10 ng/ml) and good clinical compliance to hypothyroidism. Moreover, recombinant thyrotropin stimulating hormone (rTSH) could be a preferable alternative in patients clinically unable to tolerate therapy withdrawal. A Tg cutoff level over which to perform the study seems to be 10 ng/ml, a reasonable value maintaining high accuracy in terms of a good compromise between sensitivity and specificity.