Iodine accumulation represents a differentiation marker of thyroid cancer (TC) and a cornerstone of benefits from ¹³¹I therapy. However, dedifferentiation phenotypes occur in nearly 70% of recurrent or metastatic TCs driven by oncogenic mutations such as B-Raf proto-oncogene, serine/threonine kinase (BRAF), telomerase reverse transcriptase (TERT) promoters, and tumor proten p53 (TP53). Beyond genetic alterations, epigenetics, autophagy, tumor microenvironment and other pathways are also involved in the dedifferentiation of TC and the tolerance to ¹³¹I therapy. Targeting the above-mentioned pathways has potential to improve the malignant phenotype of TC and restore sensitivity to ¹³¹I therapy, which is of great clinical significance. Based on the relevant mechanisms of dedifferentiation, this paper elaborates on the progress of preclinical experiments and clinical studies related to differentiation therapies of TC.