UNLABELLED: Chemotherapy with or without radiation is the standard therapy for anaplastic thyroid cancer (ATC), although the response rate is not high and not durable. We describe a 62-year-old male who was diagnosed with ATC and initially treated with a thyroidectomy and lymph node dissection, followed by chemotherapy. Next generation sequencing was then performed to guide therapy and the tumor was found to have BRAF and programmed death-ligand 1 (PD-L1) positivity that was subsequently treated with vemurafenib and nivolumab. This led to substantial regression of tumor nodules. Genomic sequencing-based approaches to identify therapeutic targets has potential for improving outcomes. Currently, the patient continues to be in complete radiographic and clinical remission 20 months after beginning treatment with nivolumab. KEY POINTS: Programmed death-1 (PD-1)/PD-L1 immunotherapy has shown evidence of durable responses in certain malignancies such as melanoma, lung cancer, and renal cell carcinoma.PD-L1 positive tumors promote autoimmunity against the tumor; therefore, PD-1/PD-L1 blockade may be beneficial.Molecular profiling could possibly result in improved targeted therapy for certain malignancies.