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The global food crisis is the greatest health risk currently facing humanity, but new pesticides can aid in addressing the challenge. Pyridalyl (PAL) is a synthetic insecticide with selective toxicity against Spodoptera, the world’s top pests, while causing no harmful effect for the environment, beneficial organisms (e.g. pollinators, mammals) or crops. Despite the fact that PAL represents a promising tool for sustainable food production due to this demonstrated safety and selectivity, the mechanism of action (MoA) and biological targets of the compound remain unknown. In this study, the first generation of PAL activity-based probes (ABPs) have been designed, synthesized and validated against caterpillars and caterpillar-derived Sf21 cell lines. Moreover, the probes have been used in chemical proteomics investigations of the PAL MoA and the plausibility to identify proteins responsible for in-cell activation of PAL as well as downstream targets which govern the unique PAL-driven biological response has been demonstrated. One challenge facing this study was the limited annotation of the Spodoptera genome, because of which contextualization of the PAL target profile was based on homology with Homo sapiens and Drosophila melanogaster. However, two CYP enzymes were identified as possible PAL activators, while the pathway analysis implied that PAL predominantly interacts with downstream targets involved in ATP metabolic process. This work presents an example of modern chemical biology methodology applied to unravel complex problems, identification of target lists and potential MoA’s that may help the development of new and improved pesticides that may help to alleviate the global food crisis Open Access