Thyroid cancer is the most common neoplasia of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. Its incidence has rapidly grown over the past few decades. Although most thyroid carcinomas are of the well-differentiated papillary histology, and respond well to treatment with surgical resection followed by radioactive iodine ablation, tumors with more aggressive phenotype, such as follicular, poorly differentiated, anaplastic, and medullary cancers, lead to almost 1500 patient deaths annually. Therefore, understanding molecular mechanisms that regulate the biology of these carcinomas could be helpful to identify new molecules acting as novel targets for therapeutic intervention. NF-kappaB has been recently shown to play an important role in thyroid cancer for its ability to control the proliferative and the anti-apoptotic signaling pathways of thyroid neoplastic cells. Oncogenic proteins RET/PTC, RAS and BRAF, that are involved in many aspects of thyroid carcinogenesis, can induce NF-kappaB activation in papillary, follicular, and medullary thyroid carcinomas, while constitutive de-regulated NF-kappaB activity has been found in anaplastic thyroid carcinomas. A number of NF-kappaB inhibitors have been demonstrated to induce anti-proliferative effects and/or massive apoptosis, especially in combination with radio- or chemo-therapy. The results obtained suggest that targeting NF-kappaB could be a promising strategy for advanced thyroid cancer treatment.