Anaplastic thyroid carcinoma is an extremely aggressive solid tumor that resists most therapeutic efforts and is almost always fatal. It typically arises as a terminal dedifferentiation of unrecognized long-standing differentiated thyroid carcinoma. Current chemotherapeutic agents are not capable of consistent beneficial therapeutic responses, although rare patients may gain additional months of survival. Aggressive local tumor control with surgery and external beam radiotherapy may provide palliation and delay eventual death from distant metastatic disease. This disease challenges clinicians and researchers to develop new systemic therapies as well as to aggressively treat differentiated thyroid cancers before they become anaplastic tumors.