Thyroid cancer generally has an excellent prognosis, with most patients achieving a cure through surgery and radioiodine therapy. Dedifferentiation, which results in the loss of thyroid cells' ability to uptake radioactive iodine, occurs in up to 15% of patients. Systemic therapy has improved progression-free survival in patients with radioiodine-refractory thyroid cancer and is now used in the management of progressive disease, anaplastic thyroid cancer, and in neoadjuvant settings. Molecular genetics are utilized to guide targeted systemic treatment options.