Differentiated thyroid cancer, which includes papillary and follicular histologies, is a common malignancy and is increasing in incidence. It carries a favorable prognosis compared to other cancers. However, optimal outcomes are achieved only via coordinated multimodal therapy. Of these treatments, surgery is the cornerstone of initial management. Most patients should undergo thyroidectomy with concomitant central neck (level VI) lymph node dissection. On the other hand, thyroidectomy alone may be appropriate for patients with smaller tumors (T1 or T2) and no evidence of suspicious lymphadenopathy. Surgery is also indicated in cases of cervical lymph node metastases and locoregional recurrence. The principal adjuvant therapy is radioactive iodine, which should be considered in patients with a high risk of locoregional recurrence or with metastatic disease. Similarly, suppression of endogenous thyroid-stimulating hormone is recommended in patients with an elevated risk of recurrence. External-beam radiotherapy is indicated in patients with gross extrathyroidal extension or residual disease not amenable to surgery. Finally, molecular therapies, especially those targeting key tyrosine kinases and/or inhibiting angiogenesis, are emerging treatment modalities that could replace the limited efficacy of conventional chemotherapy. Copyright © 2010 Elsevier Inc. All rights reserved.