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Patients with radioactive iodine (RAI) refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis. This article reviews the definition of RAI-refractory thyroid cancer and the management approach. Watchful waiting should be considered for patients with asymptomatic and non-progressive disease, while oral targeted agent with tyrosine kinase inhibitors can be considered for patients who are symptomatic or whose disease would cause irreversible complications if treatment has not been initiated. Since these targeted agents only improve disease-free survival and are associated with adverse events, physicians should assess both clinical and tumor factors carefully to decide on the right timing of start of palliative treatment., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)