Chemical proteomics is now ubiquitous throughout the field of chemical biology. The broad scope of the technique towards myriad biological questions render it incredibly useful in diverse investigations into proteomes existing in various conditions. Efforts towards expanding the druggable proteome and improving sample preparation and data acquisition are constantly ongoing in response to the demand for progress. By implementing sample multiplexing and a redesigned lysine-targeting probe, we streamline a quantitative, direct mapping of global reactivity and ligandability of proteinaceous lysines in human cells. Leveraging this framework, we identify numerous lysine−meroterpenoid interactions in breast cancer cells at tractable protein sites across diverse structural and functional classes, including those historically deemed undruggable. Through a case study of lysine-reactive natural products, we demonstrate the ability of chemoproteomics platforms such as ours to uncover new mechanisms of action for protein targets through unexplored reactivity of lysines. Similarly, we took a targeted approach to an essential enzyme, bile salt hydrolase (BSH), but designed a chemoproteomics workflow to profile the inactive form of the enzyme that we determined to be a cysteine-sulfenic acid. Through taking advantage of this newfound mechanism of action, we were able to identify microbes expressing redox-reactive BSH as a form of post-translational regulation by profiling the murine gut microbiome with probes specific for cysteine oxidation states (thiol versus sulfenic acid). Collectively, this work demonstrates the importance of innovation in chemical proteomics approaches in both the chemotypes and reactivity pursued, and the sample preparation and quantitation techniques. Uncovering mechanisms of action that can be used to profile protein targets in various physiological models holds great importance in furthering our understanding of molecular machinery that drives biology.