Abstract: The conventional treatment options for differentiated thyroid carcinoma (DTC) include surgery, radioactive iodine therapy, and thyroid-stimulating hormone suppression therapy. Most DTC patients respond well to aforementioned treatments; however, some patients develop iodine-refractory differentiated thyroid cancer (RAIR-DTC) due to the dedifferentiation of the sodium iodide symporter (NIS), which is generally associated with poorer prognosis. The authors review the mechanism of action of NIS, the various signaling pathways and the molecular networks mechanisms which governing NIS activity, pointing out that developing therapeutic agents based on molecular research findings on NIS represents a promising direction for future RAIR-DTC treatment.