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Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18 + column, under a gradient of 10% acetic acid in water/acetonitrile. An Acquity-TQD (R) with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis (R) MCX microElution) before injection in the system. Calibration curves ranges from 0.4 to 100 mu g/ml for vemurafenib, from 1 to 1000 ng/ml for dabrafenib, from 0.5 to 500 ng/ml for cobimetinib and binimetinib, and from 0.75 to 250 ng/ml for trametinib. At all concentrations the bias was within +/- 15% of the nominal concentrations and precision was 15%. All results were within the acceptance criteria of the EMA guidelines on method validation. This rapid, sensitive and specific UPLC-MS/MS method can perform simultaneous quantification of targeted therapies used in malignant melanoma and is usable for routine TDM.