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The discovery of the anticancer activity of cisplatin and its clinical application has opened a new field for studying metal-coordinated anticancer drugs. Metal-based anticancer drugs, such as cisplatin, can be transported to cells after entering into the human body and form metal–DNA or metal–protein adducts. Then, responding proteins will recognize adducts and form stable complexes. The proteins that were binding with metal-based anticancer drugs were relevant to their mechanism of action. Herein, investigation of the recognition between metal-based anticancer drugs and its binding partners will further our understanding about the pharmacology of cytotoxic anticancer drugs and help optimize the structure of anticancer drugs. The "soft" ionization mass spectrometric methods have many advantages such as high sensitivity and low sample consumption, which are suitable for the analyses of complex biological samples. Thus, MS has become a powerful tool for the identification of proteins binding or responding to metal-based anticancer drugs. In this review, we focused on the mass spectrometry-based quantitative strategy for the identification of proteins specifically responding or binding to metal-based anticancer drugs, ultimately elucidating their mechanism of action. [ABSTRACT FROM AUTHOR]