This article presents an overview of medical management of persistent or recurrent differentiated thyroid cancer, in particular focusing on monitoring strategy and treatment plans. Most patients with differentiated thyroid carcinoma can be successfully rendered to be free of disease with initial treatments, and those with persistent or recurrent disease can still expect long-term survival when they are monitored properly and treated accordingly. Along with serum thyroglobulin, neck ultrasonography, and radioactive iodine whole-body scans, the use of cross-sectional imaging studies and (18F) fluoro-2-deoxy-D-glucose-positron emission tomography have facilitated the effort in localizing lesions and traditional treatments can be implemented effectively. For disease resistant to conventional therapies, there are new treatment modalities emerging and being tested, including several agents targeting specific signaling pathways, each of which may offer the potential remedy.