Despite more than 50 years of research, the overall clinical outcomes of patients afflicted with anaplastic thyroid cancer remain dismal. Survival is limited by the dire consequences of an uncontrolled primary and the prevalence of overt or occult distant metastasis. Local control is influenced by multiple confounding variables, including the inherent biological aggressiveness of the disease and the seemingly insurmountable technical obstacles to both surgery and radiotherapy. In response to these challenges, revolutionary changes in the treatment paradigm over the last 20 years, specifically the adoption of a multimodal treatment strategy, suggest improvements in local control and short-term median survival and have changed the pattern of progression, even for patients presenting with locally advanced disease. For the first time there is attestation of even long-term survivorship for a few patients who harbor advanced local, but nonmetastatic, disease. The current challenge is to address the high incidence of apparent or occult distant metastasis. Newly developed targeted therapies are likely to change the treatment paradigm, and they hold the promise of being able eventually to make treatment with curative intent available to some patients.