Abstract: The majority patients of differentiated thyroid carcinoma (DTC) with indolent progression have general good prognosis after standard primary treatments including surgery, thyroid stimulating hormone (TSH) suppression and radioactive iodine (RAI) therapy. However, there are still some patients suffered from recurrence or distant metastasis after initial treatment. They may lose the ability of uptaking iodine during their natural course of disease or treatment and could not benefit from subsequent RAI treatment, which will result in radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). Options are very limited for RAIR-DTC patients, which is associated with a poor prognosis. Recently, with the research advances on the molecular mechanism of RAIR-DTC, redifferentiation combined with RAI therapy have been increasingly used to treat RAIR-DTC, and some outcomes are quite encouraging. This paper reviews the progress of signaling pathway inhibitors, histone deacetylase inhibitors, DNA methyltransferase inhibitors, retinoids and peroxisome proliferator-activated receptor agonists in redifferentiating therapy of RAIR-DTC.