Differentiated thyroid carcinoma (DTC) accounts for more than 90% of new thyroid cancer diagnoses, and includes papillary, follicular and Hürthle cell carcinoma. The prognosis for the vast majority of individuals diagnosed with DTC is excellent, with current treatment that includes surgery, radioactive iodine ablation and postoperative thyroid-stimulating hormone suppression. Unfortunately, the small proportion of individuals who develop radioactive iodine-resistant recurrent disease have few treatment options, and the vast majority will eventually die from their disease. Recently, several novel targets for anticancer agents have been identified and offer new hope for thyroid cancer patients diagnosed with progressive disease. In addition to targeting genes commonly altered in thyroid cancer, which include mutations in BRAF, RAS and RET, proangiogenic growth factor receptors and the sodium-iodide symporter have also been targeted. Several clinical trials evaluating tyrosine kinase and angiogenesis inhibitors for treatment of individuals diagnosed with metastatic or treatment-refractory DTC are currently underway. The objective of this review is to evaluate recent clinical trials that have studied novel targeted drugs for treatment of DTC.