Lorenzo Gerratana,1,2 Giovanna De Maglio,3 Alessandro De Pellegrin,3 Alessandro Follador,1 Karim Rihawi,1,2 Stefano Pizzolitto,3 Fabio Puglisi,1,2 Gianpiero Fasola1 1Department of Oncology, University Hospital of Udine, 2Department of Medical and Biological Sciences, University of Udine, 3Department of Pathology, University Hospital of Udine, Udine, Italy Abstract: Molecular characterization is increasingly changing clinical practice, in both diagnosis and treatment. BRAF is a proto-oncogene that is mutated in ~2%–4% of lung cancers, but the incidence rises to 40%–45% among papillary thyroid cancers. Furthermore, BRAF is a promising target in lung cancer treatment. The present case study covers both the challenges of molecular differential diagnosis and the perspectives opened by targeted therapy by discussing the history of a 78-year-old female affected by a papillary histotype carcinoma with BRAF mutation associated with both thyroid and lung localizations. A differential diagnosis was possible as a consequence of a multidisciplinary approach including an in-depth molecular characterization. Based on this molecular feature, the patient was successfully treated with the BRAF inhibitor dabrafenib after the failure of treatment with standard regimen. To the best of our knowledge, this is the first published case of non-small-cell lung cancer with metastasis to thyroid and with BRAF V600E mutation. Keywords: BRAF mutation, molecular diagnosis, target therapy