Radioiodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC) following total thyroidectomy. Nevertheless, about 5% of patients with DTC are RAI-refractory (RAI-R). Understanding the molecular mechanisms associated with DTC during progression towards RAI-R DTC, including thyroid-stimulating hormone levels, may help to explain the pathophysiology of challenging RAI-R DTC clinical cases.