Daniel C McFarland,1 Krzysztof J Misiukiewicz2,31Division of Hematology and Medical Oncology, Mount Sinai Medical Center, New York, NY, USA; 2Division of Hematology and Medical Oncology, 3Department of Otolaryngology, Mount Sinai Medical Center, Ruttenberg Treatment Center, New York, NY, USAAbstract: Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials.Keywords: tyrosine kinase inhibitors, targeted therapy, RAI DTC, novel thyroid cancer treatment