Thyroid iodide uptake is essential for the clinical application of radioiodine in patients with well-differentiated thyroid carcinoma. Iodide uptake occurs across the plasma membranes of thyroid follicular cells and cancer cells via an active transporter process mediated by sodium iodide symporter (NIS). The cloning of the NIS gene enabled the molecular mechanisms underlying iodide transport to be better characterized, and thus, opened the way to the expansion of its role in thyroid carcinoma. Thyroid-stimulating hormone (TSH) is the principal regulator of iodide uptake, although many other factors, including insulin, insulin-like growth factor I, epidermal growth factor, and iodide itself, also influence iodide uptake by the thyroid gland. Human NIS expression may be increased, decreased, or absent in well-differentiated thyroid cancer. However, the reason for reduced iodide uptake in well-differentiated thyroid carcinoma is not solely due to lower NIS expression, and probably depends on a complex combination of regulatory changes that ultimately affect NIS expression, targeting, or activation. Nevertheless, reduced functional levels of NIS on cell membranes do account for the reduced iodide uptake observed in thyroid carcinoma. Furthermore, thyroid cancer tissues expressing NIS take up more I-131 than those not expressing NIS, and these tumors subsequently show a higher rate of response to radioiodine therapy. Accordingly, NIS appears to have the potential to expand the role of nuclear medicine in the management of thyroid carcinoma.