Abstract: Investigating the interactions of anticancer metallodrugs with proteins, as well as their effects on the process of drug transport, cellular uptake, metabolism and bioavailability, is very important for structure-based design, improvement of activity and reduction of side effects of anticancer metallodrugs. The soft ionization mass spectrometry including ESI and MALDI can greatly preserve the coordination of drug molecules to biomolecules during the performance, and provide direct information on the binding sites of metallodrugs on proteins. Additionally, mass spectrometry has many advantages such as high sensitivity, low sample consumption, speed, suitable for complex biological samples and so on. Thus, it has become the most powerful tool for studying the interactions of anticancer metallodrugs with proteins. The increasing researches on this field provide not only valuable chemical and biological information for drug discovery, but also greatly promote mass spectrometry itself. Bases on the update progress of our own group on the interactomic studies of anticancer metallodrugs, we presents a review of the latest achievements of research on the interactions of platinum and ruthenium-based anticancer drugs (or candidates) with proteins using bottom-up and top-down mass spectrometric approaches. A brief analysis on the possible future research trends and development in this area is also given.