Abstract: For well-differentiated and early-stage thyroid cancer, conventional treatment options such as surgery, thyroid-stimulating hormone suppression therapy, and radioactive iodine therapy can usually significantly extend patients’ overall survival and progression-free survival, with prognosis approaching that of the general population. In contrast, for advanced or undifferentiated thyroid cancer that cannot be surgically resected or is unresponsive to radioactive iodine treatment, systemic therapy is typically required. Traditional cytotoxic chemotherapy or external radiation therapy has limited efficacy in these patients. Over the past decade, targeted therapies for thyroid cancer have undergone rapid development. Despite these treatments yielding promising results, many patients with advanced thyroid cancer ultimately experience disease progression due to acquired resistance. In this paper, we summarize the mechanisms of resistance to targeted drugs in thyroid cancer and explore strategies to overcome resistance, aiming to provide reference for future clinical practice in targeted therapy and guide directions for subsequent research.