PURPOSE OF REVIEW: Recent advances in the understanding of the biological basis for thyroid cancer have identified molecular changes in thyroid cancer cells. These changes form the basis for targeted therapies, which have been investigated with some success in patients with advanced, inoperable thyroid cancers and are the subject of this review. RECENT FINDINGS: For patients with advanced differentiated thyroid cancers, sorafenib, selumetinib, pazopanib and sunitinib have been investigated with promising results. In the setting of advanced medullary thyroid cancer, vandetanib now has FDA approval, whereas sorafenib, sunitinib and cabozantinib have shown activity in early studies. For patients with anaplastic thyroid cancer, no targeted therapy has been proven to be effective in vivo, although preclinical work on various kinase inhibitors has shown promise. Despite the potential for disease response, significant cardiac, gastrointestinal and skin-related side effects are reported for all therapies, limiting their application outside the setting of incurable disease. SUMMARY: Inoperable thyroid cancer still has a poor prognosis, however, the introduction of targeted therapies offers the hope of longer quality of meaningful life for this small group of patients.