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TCI strategies to target more common amino acid side\u2010chains have yet to be demonstrated. Targeting other amino acids would also expand the pharmaceutical industry\u2018s toolbox for targeting other tough\u2010to\u2010drug proteins. We report herein a glyoxal\u2010based, arginine\u2010reactive strategy to generate potent and selective small\u2010molecule TCIs of Mcl\u20101 (an important anti\u2010apoptotic protein) by selectively targeting the conserved arginine (R263) in the protein. We further validated the generality of this strategy by developing glyoxal\u2010based, irreversible covalent inhibitors of AURKA (a cancer\u2010related kinase) that showed exclusive reactivity with a solvent\u2010exposed arginine (R220) of this enzyme. We showed the resulting compounds were potent, selective and cell\u2010active, capable of covalently engaging endogenous AURKA in MV\u20104\u201311\u2005cells with long residence time. 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