The incidence of thyroid cancer in the United States is increasing. The emergence of immunotherapies and targeted therapies involving the PI3K/Akt/mTOR and MAPK cell signaling pathways, which are most often implicated in thyroid cancer, has changed the landscape of treatment for radioactive iodine refractory and metastatic disease. The multikinase inhibitors lenvatinib, sorafenib, and cabozantinib, targeted inhibitors for BRAF, RET, and TRK, and immunotherapies in combination with tyrosine kinase inhibitors (TKIs) have demonstrated significant treatment efficacy. Cytotoxic chemotherapy is generally not recommended but may have limited utility in treating disease refractory to TKI therapy and for improving radiosensitivity for external beam radiation therapy. Current areas of active investigation include redifferentiation of thyroid cancer for the restoration of radioactive iodine uptake, BRAF inhibitor resistance, identification of predictive biomarkers for immunotherapy, and the optimal sequencing of targeted therapies.