Four proto-oncogenes commonly associated with well-differentiated thyroid carcinoma, rearranged during transfection (RET)/papillary thyroid cancer, BRAF, RAS, and PAX8/peroxisome proliferator activated receptor-gamma, may carry diagnostic and prognostic significance. These oncogenes can be used to improve the diagnosis and management of well-differentiated thyroid carcinoma. Limited therapeutic options are available for patients with metastatic well-differentiated thyroid cancer, necessitating the development of novel therapies. Vascular endothelial growth factor (VEGF)- and RET-directed therapies such as sorafenib, motesanib, and sunitinib have been shown to be the most effective at inducing clinical responses and stabilizing the disease process. Further clinical trials of these therapeutic agents may soon change the management of thyroid cancer.