Abstract：Genome sequencing projects have revolutionized our view of the complexity of prokaryotic and eukaryotic proteomes, however, we are also left with a daunting challenge of functionally annotating these large number of predicted proteins. Chemical proteomic methods, such as activity-based protein profiling (ABPP), have been developed aiming at systematically discovering new functional targets directly from native proteomes. In this talk, I will present recent progresses from my laboratory which combine ABPP-based chemical proteomic, biochemical and computational strategies to uncover functional sites of post-translational modifications by reactive metabolites in proteomes.