α,β-unsaturated carbonyl moieties react with nucleophiles, and the most nucleophilic groups of a protein are amines (lysine side chains or the N-terminal amino group) and thiols (from the side chains of cysteine residues). The acidity of thiols and the higher nucleophilicity of sulfur make Michael reactions with thiols more favorable than for amines and determine the bias of α,βunsaturated carbonyl compounds for cysteine residues over lysine residues. The electron deficiency of the carbonyl compound (or more generally, the alkene or alkyne substituent) helps to determine its reactivity as a covalent inhibitor. Nitro compounds tend to be more highly electrondeficient than ketones or aldehydes, which are in turn more electron-deficient than unsaturated sulfones or amides. Unsaturated carboxylic acids are generally resistant to Michael addition because deprotonation of acids is facile and the anions formed from their deprotonation sate the electron-deficiencies of the remaining carbonyl group. High reactivity with nucleophiles is likely to render the warhead less selective, both with the type of nucleophile and with the enzyme target, while low reactivity may mean that the warhead cannot react with the target, and so α,βunsaturated carbonyl compounds with intermediate reactivities are great options for warheads. A majority of covalent inhibitors using α,β-unsaturated carbonyl moieties as warheads rely on α,βunsaturated amides. Amides are some of the least electron-deficient carbonyl compounds, tempering the olefin's reactivity, but are sufficiently reactive to undergo Michael addition with biological nucleophiles. In addition, amides are easily prepared with a variety of nitrogen substituents and amide couplings are some of the most common reactions in medicinal chemistry. The distance of nitrogen substituents from the reactive sites of unsaturated amides allows unfettered substitution; unsaturated amides can be assembled from unsaturated carboxylic acids or their derivatives and readily prepared amines, allowing covalent inhibitors to be prepared with separate warhead and binding modules and with a wide variety of structures.