Natural products have traditionally been a fruitful source of chemical matter that has been developed into novel therapeutics. Actinomycetes and several other bacterial taxa are especially gifted in biosynthesizing natural products. However, many decades of intense bioactivity-based screening led to a large rediscovery problem, rendering industrial natural product discovery pipelines uneconomical. Numerous methods for circumventing the rediscovery problem have been developed, among them various chemistry-focused strategies, including reactivity-based screening. Emerging from the field of chemical proteomics, reactivity-based screening relies on a reactive probe that chemoselectively modifies a functional group of interest in the context of a complex biological sample. Reactivity-based probes for several distinct functional groups have been deployed to discover new polyketide and peptidic natural products. This chapter describes the protocols to conduct a reactivity-based screening campaign, including bacteria cultivation and screening of cellular extracts with phenylglyoxal-, tetrazine-, thiol-, and aminooxy-functionalized probes, which respectively target primary uriedo, electron-rich olefins, Michael acceptors, and reactive carbonyls. In addition, a recent case study is presented that employs reactivity-based screening as a component of a forward genetics screen to identify a previously unknown peptidyl arginine deiminase. We anticipate that these methods will be useful for those interested in discovering natural products that evade detection by traditional, bioassay-guided methods and others who wish to rapidly connect metabolic chemotype with genotype.