Thyroid nodules are extremely common in the general population. The differential diagnosis includes numerous entities, non-neoplastic and neoplastic, benign and malignant. However, the diagnosis of follicular-patterned lesions remains an area fraught with controversy and diagnostic criteria are highly variable. It is, therefore, a field in need of objective, scientific markers that better characterize these lesions than has been possible by classical morphology. A number of candidates have been proposed. No single marker can identify all malignant follicular-patterned lesions, however, various combinations have been proposed. They include HBME-1, high molecular weight cytokeratins and ret, galectin-3 and TPO, galectin-3, fibronectin-1, CITED-1, HBME-1, and CK19. Advances in our understanding of the molecular basis of thyroid cancer will allow the identification of new markers and more accurate characterization of specific subtypes of neoplasia and malignancy. As new markers are characterized and validated, directed by molecular profiling of thyroid lesions with characteristic morphology, behavior, and outcome, they will become available as routine immunohistochemical markers that will provide a more accurate, scientific, and clinically relevant consultation report from the pathologist for cytology and surgical pathology procedures. Application of these markers will enhance the diagnosis of thyroid nodules and better guide the management of patients with these lesions.