The study by Wagle et al. investigates the mechanisms of resistance to RAF inhibition in BRAF-mutant melanoma, a common and challenging scenario in cancer therapy. The authors performed targeted, massively parallel sequencing of 138 cancer genes in a patient's tumor that developed resistance to the RAF inhibitor PLX4032 after an initial response. They identified an activating mutation (MEK1CT215) in the downstream kinase MEK1, which was absent in the pretreatment tumor. This mutation increased MEK1 kinase activity and conferred robust resistance to both RAF and MEK inhibition in vitro. The study highlights the importance of understanding resistance mechanisms to develop effective treatment strategies and underscores the utility of emerging genomic technologies in personalized cancer medicine. The findings provide a framework for assessing mechanisms of acquired resistance to kinase inhibitors and suggest that combining RAF and MEK inhibitors may be necessary to overcome resistance.The study by Wagle et al. investigates the mechanisms of resistance to RAF inhibition in BRAF-mutant melanoma, a common and challenging scenario in cancer therapy. The authors performed targeted, massively parallel sequencing of 138 cancer genes in a patient's tumor that developed resistance to the RAF inhibitor PLX4032 after an initial response. They identified an activating mutation (MEK1CT215) in the downstream kinase MEK1, which was absent in the pretreatment tumor. This mutation increased MEK1 kinase activity and conferred robust resistance to both RAF and MEK inhibition in vitro. The study highlights the importance of understanding resistance mechanisms to develop effective treatment strategies and underscores the utility of emerging genomic technologies in personalized cancer medicine. The findings provide a framework for assessing mechanisms of acquired resistance to kinase inhibitors and suggest that combining RAF and MEK inhibitors may be necessary to overcome resistance.