Background: About 50% of papillary thyroid cancers, the most common type of all thyroid malignancies, harbor the BRAFV600E mutation. The prognostic value of this mutation is still under debate, but according to many studies, the BRAF mutation significantly downregulates genes involved in the iodine metabolism of tumor follicular cells. This mutation can be also found in some dedifferentiated and anaplastic thyroid cancers, which raises the issue of the selective advantage of novel targeted therapies. Aim: The aim of this review is to discuss the significance of the BRAF mutation mostly in radioiodine-refractory thyroid cancers (RR-TC) with respect to recent preclinical and clinical studies reporting the results of different RAF and MEK inhibitors. Conclusions: BRAF mutation detection in progressive RR-TC could play a role in decision-making of targeted therapies in the near future. So far, only multi-kinase inhibitors (sorafenib and lenvatinib) are legally accepted. On the other hand, for patients with disseminated BRAF mutant malignant melanoma or lung cancer, selective treatments with RAF and MEK inhibitors (vemurafenib, dabrafenib, and trametinib) are available. A crucial advantage of these inhibitors in the treatment of thyroid cancer is their ability to restore expression of the genes involved in iodine metabolism in cancer cells that have lost this ability, thus opening the door for radioiodine treatment again.