Radioactiveiodine (radioiodine) therapy is a standard and effective therapeutic approachfor high-risk differentiated thyroid carcinomas based on the unique ability ofthe thyroid follicular cell to accumulate iodide through the sodium/iodidesymporter (NIS). However, a recurrent limitation of radioiodine therapy is thedevelopment of radioiodine-refractory differentiated thyroid carcinomas, whichare associated with a worse prognosis. Loss of radioiodine accumulation inthyroid carcinomas has been attributed to cell dedifferentiation, resulting inreduced NIS expression and NIS intracellular retention involvingtranscriptional and post-transcriptional or post-translational mechanisms,respectively. Emerging therapies targeting oncogene-activated signal pathwayspotentially involved in thyroid carcinogenesis recover radioiodine accumulationin radioiodine-refractory tumors constituting the rationale ofredifferentiation therapies. Here, we will comprehensively discuss themolecular mechanisms underlying radioiodine therapy, refractoriness toradioiodine therapy in differentiated thyroid carcinomas and novel strategiesfor restoring radioiodine accumulation into radioiodine-refractory thyroidcarcinomas.