The clinical application and development of potent metal-based drugs relies heavily on a full understanding of their underlying molecular mechanisms. The emerging research field of metalloproteomics for unveiling the correlation between metals and biological proteomes has received growing attention and has been successfully implemented in medicinal inorganic chemistry. In this article, we introduce recent progress in the mechanistic studies of representative metal-based drugs by using state-of-the-art metalloproteomic approaches, with a focus on how the application of analytical chemistry, biocompatible chemical probes, and integrative omits help to advance the knowledge of metallodrug targeting profiles within a systemic perspective.