Combination therapy with BRAF-V600E and MEK inhibitors is under investigation to overcome resistance to BRAF-V600E inhibitors. However, one-third of patients receiving this combination progress within 6 months. To identify possible mechanisms of resistance, Long et al. analysed 20 melanoma metastases with BRAF-V600E from 10 patients treated with dabrafenib (a BRAF-V600E inhibitor) and trametinib (a MEK and ERK inhibitor). They found MAPK reactivation through BRAF amplification and activating mutations of NRAS and MEK2. Interestingly, whereas MEK2-C125S mutation conferred resistance to the combination therapy, the equivalent MEK1-C121S mutant did not, highlighting a possible unique function of MEK2. As mutations in the MAPK and PI3K pathway are often already present in BRAF-V600E-mutant melanoma, the authors raise caution about combining BRAF-V600E inhibition with inhibitors of either of these pathways.