Mortality rates from thyroid cancer have fallen significantly in recent decades, almost certainly as the result of earlier diagnosis and improved treatment of differentiated (papillary and follicular) thyroid cancer. Enhanced survival is likely a result of early diagnosis and therapy applied at a disease stage when treatment is most effective. In the United States and Europe, most patients at high risk for relapse and death from thyroid cancer are treated with total or near-total thyroidectomy and receive radioiodine ablation of residual normal or malignant thyroid tissue, followed by treatment with thyroid hormone, a strategy that cures more than 80% of patients. Still, some die of the disease and nearly 15% have local recurrences, while another 5% to 10% develop distant metastases. Over 50% of recurrences appear in the first five years, but distant metastases may surface years, and sometimes decades, after initial therapy. Much has been learned about risk stratification to predict recurrence and death from thyroid cancer but individual patients continue to have adverse outcomes not always foreseen by a low tumor stage. Follow-up must accordingly be meticulous and prolonged. The National Cancer Center Network (NCCN) has recently established consensus practice guidelines that give explicit advice about the diagnosis and management of benign and malignant thyroid tumors, including paradigms for long-term follow-up and the treatment of recurrent disease. The guidelines confirm that diagnostic scanning with 131I and measurement of serum thyroglobulin (Tg) levels are the mainstay of follow-up, offering the opportunity to detect recurrent or persistent cancer at very early stages. These guidelines advocate TSH-stimulated serum Tg measurements, done either during thyroid hormone withdrawal or stimulation with recombinant human TSH (rhTSH, Thyrogen), that often identify the presence of cancer well before diagnostic whole-body scanning or other imaging studies can spot the tumor, which offers the opportunity to treat recurrent disease at an early stage. The use of rhTSH adds a new dimension to long-term follow-up that avoids putting patients through the symptoms of hypothyroidism, and offers the opportunity to follow some patients with rhTSH-stimulated serum Tg levels without performing 131I whole-body scans. A multicenter international study has shown that serum Tg measurements alone are not as sensitive in the identification of patients with persistent or recurrent tumor as are rhTSH-stimulated serum Tg determinations. Although not yet approved for preparation of patients for 131I therapy, rhTSH has been used successfully in a compassionate use program for this purpose in a relatively large number of patients. Formal clinical investigations now planned to provide guidelines for the use of rhTSH for therapeutic 131I portend a new set of effective therapeutic paradigms for the management of differentiated thyroid cancer.