Anaplastic thyroid cancer (ATC) is considered to be one of the most virulent, treatment refractory, malignancies. Recent molecular insights into the biology of thyroid cancer have transformed ATC management and BRAF/MEK targeted therapy is now incorporated into guideline based multidisciplinary care. We report visceral perforation in the setting of an extreme response to such therapy in a patient with a mixed papillary thyroid carcinoma and ATC. Molecularly targeted therapy afforded a dramatic, but life-threatening, response to treatment. This report highlights the complexities of care for the patient and treating clinicians.