Conventional affinity-based covalent capture technologies rely on the use of chemical-or photochemical-based cross-linker groups that, when appended to a pharmacophore of interest, enhance identification of their binding targets and molecular mechanisms (Figure ). In particular, photoaffinitiy labeling (PAL) through use of the diazirine, a unique three-membered ring containing N=N bond, has emerged as a highly useful option due to its small size and high reactivity (Figure ). Comparatively, the relatively inert nature of diazirine until photoactivation makes it far preferrable to chemical cross-linkers that are always activated and cause background labeling issues. However, despite its widespread adoption, the activation of diazirines relies on the use of high energy UV light, generating multiple reactive moieties such as carbenes and diazo species with differing bio-reactivity profiles that can complicate downstream proteomic analysis and target identification. Herein we present an electroaffinity labeling ("ECAL") platform technology in live cells (Figure ). The method relies on a similarly small functional group rarely explored in organic synthesis, a diazetidinone (DZE), that enables chemoproteomic-based target identification of pharmacophores within complex cell environments (Figure ). To showcase ECAL, we profiled DZE analogs of well-validated ligands as well as a previously unexplored REV-ERBα [also known as NR1D1 (nuclear receptor subfamily 1 group D member 1)] agonist in live cells. Recent studies have revealed REV-ERBα as a potential drug target due to its broad role in pathologies such as sleep disorder, metabolic syndrome, heart failure, cancer, and inflammation. Its putative ligands, SR-9009 and SR9011, have been utilized to elicit various pharmacological activities in multiple in vitro and in vivo disease-phenotypes. However, despite the wide-ranging biological implications, chemoproteomic validation of REV-ERBα as the target for these ligands has not been reported.