To provide insight into the molecular nature of the clinical responses seen with MAPK pathway inhibition in melanoma, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAFV600E inhibitor PLX4032 (vemurafenib) and the MKK1/2 inhibitor AZD6244 (selumetinib).. In three replicate experiments, we quantified a total of 23,986 phosphosites on 4,722 proteins. This included 1,317 phosphosites that reproducibly decreased in response to at least one inhibitor.