Although thyroid nodules are common, few are malignant and require surgical treatment. A systematic approach to their evaluation is important to avoid unnecessary surgery. Fine-needle aspiration biopsy has resulted in substantial improvements in diagnostic accuracy, cost reductions, and higher malignancy yield at time of surgery. The preferred approach when repeated fine-needle aspiration biopsy fails to yield an adequate specimen remains a challenge. Management of patients with nodules "suspicious for follicular neoplasm" is difficult, since only 15% to 20% of such lesions have been shown to be malignant. Immunohistochemical markers, such as galectin-3 and human bone marrow endothelial cell (HBME-1), have shown promise in preliminary studies. Routine calcitonin measurement in patients with thyroid nodules has been advocated for early detection of medullary thyroid cancer. However, the low frequency of this cancer, coupled with the high cost associated with case detection, has resulted in a lack of general acceptance of this recommendation.