Mass spectrometry offers an increasingly useful approach to gain a protein-centric view of cancer signaling and progression. For translational cancer research we are interested in predicting and understanding cellular response to targeted therapies. In BRAF cancers (thyroid, melanoma) we used phosphoproteomics to identify activities of specific kinases in response to drug inhibitors and development of drug resistance. This revealed protein kinase CK2 as an important new target, whose inhibition provides highly synergistic anti-proliferative effects with BRAF inhibitors [1]. Basal level protein expression can also be used to predict response of cancer cells to drugs. We applied SWATH-MS to a panel of early passage Stage III melanoma cell lines to show that expression of particular proteins accurately predicts response to MAPK inhibitors independently of genotype. Thus, clinical use of such an approach could be more useful than the current standard of care which is centred on mutational genotype alone.