Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in "differentiated thyroid cancers" remains a clinical problem despite optimized RAI administration protocols. Functional and associated are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols.