Montero-Conde and colleagues show that BRAF-mutant thyroid cancer cells are resistant to RAF and MAP/ERK (MEK) inhibitors. Reactivation of RAS signaling in these cells was associated with de-repression of HER3 transcription due to decreased binding of C-terminal binding protein 1 and 2 (CTBP1/CTBP2) to the HER3 promoter. RAF/MEK inhibition also triggered increased HER3 phosphorylation and activation of HER2/HER3 heterodimers specifically in BRAF-mutant thyroid cancer cells. This effect was dependent on autocrine production of the HER3 ligand neuregulin 1 in thyroid cancer cells, identifying a lineagespecific mechanism of MAPK inhibitor resistance. Treatment with lapatinib sensitized thyroid cancer cells to RAF/MEK blockade and inhibited the growth of murine thyroid tumors, suggesting that this combination may overcome resistance in patients with thyroid cancer. For details, please see the article by Montero-Conde and colleagues on page 520.