Neoadjuvant therapy for advanced thyroid cancer is a dynamic area of investigation. Patient candidacy, optimal timing of treatment initiation, and duration of treatment are not yet defined. Several factors guide therapy selection and impact treatment response, including tumor type, underlying molecular alteration(s), and extent of tumor burden. This chapter will explore the emerging body of evidence for neoadjuvant use of targeted therapy and immunotherapy in treatment of advanced thyroid cancer, addressing patient selection, the role of molecular profiling in treatment decision-making, recommended treatment duration, treatment-associated complications and expected clinical outcomes.