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Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Conventional chemotherapy acts through inducing toxic effects on dividing cells, resulting in damage of tumor cells, but also of normal tissues. Therefore, side effects like myelosuppression, alopecia and gastrointestinal symptoms are frequent. The optimum goal of anticancer therapy is the discovery of drugs that specifically kill malignant cells and cause no or little side effects. Targeted therapy refers to a new generation of cancer drugs designed to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progression. Therefore, the objective of this therapy is to disrupt pathways that are inappropriately activated in cancer cells. This type of treatment has been applied specially to oncogenic protein kinases. Antisense drugs, monoclonal antibodies and small-molecule drugs are examples of therapy intercepting important molecules in tumors and are being used in clinical trials. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer.