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No effective systemic treatment currently exists for iodine\u2010refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. <jats:italic>RET<\/jats:italic> (rearranged during transfection)\/<jats:italic>PTC<\/jats:italic> (papillary thyroid carcinoma) gene rearrangements, <jats:italic>B\u2010Raf<\/jats:italic> gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR\u20102) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi\u2010kinase inhibitors such as axitinib, sorafenib, motesanib, and XL\u2010184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer. \u00a9 2011 Wiley Periodicals, Inc. 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