A variety of covalent inhibitors use α,β-unsaturated carbonyl moieties as their warheads; second only to β-lactams. The kinase inhibitors afatininb, ibrutinib, osimertinib, olmutinib, adagrasib, sotorasib, dacomitinib, acalabrutinib, zanabrutinib, neratinib, and futibatinib (all US FDA-approved medications; Supplementary table ) rely on unsaturated amides as warheads, as well as the failed drug candidate rociletinib (Supplementary table ). Most α,β-unsaturated carbonyl containing covalent inhibitors rely on either terminally unsubstituted or substituted with a single alkyl group because steric hindrance deters Michael addition. Abiraterone and omaveloxolone are exceptions to this observation; both compounds contain more highly substituted α,βunsaturated ketone moieties (Supplementary table ). The increased steric hindrance of the olefin moiety in α,β-unsaturated ketones is likely countered by the greater electron-deficiency as compared to α,β-unsaturated amides. Dimethyl fumarate (Tecfidera), used in the treatment of multiple sclerosis, is an electron-deficient unsaturated ester (Supplementary table ) whose actual mechanism of action is unknown though covalent modification via Michael addition is one plausible mechanism.