Targeted covalent inhibitors possess advantages over reversible binding drugs, that include higher potency, enhanced selectivity and prolonged pharmacodynamic duration. The standard paradigm for covalent inhibitor discovery relies on the use of α,β-unsaturated carbonyl electrophiles to engage the nucleophilic cysteine thiol, but due to its rarity in binding sites, the amino acid is often not available for targeting. 10 years ago we highlighted the emerging potential of sulfonyl fluoride chemical probes that were initially found to serendipitously modify residues beyond cysteine, including tyrosine, lysine, histidine, serine and threonine. Since then, the rational application of sulfonyl fluorides and related sulfonyl exchange warheads to site-specifically target diverse amino acid residues in proteins using small molecules, oligonucleotides, peptides and proteins, has made considerable progress, which has significantly advanced covalent therapeutic discovery. Additionally, sulfonyl exchange chemistry has recently shown utility in the labeling of RNA and carbohydrates, further expanding the biomolecular diversity of addressable targets. This Perspective provides not only a timely update regarding this exciting area of research, thus serving as a useful resource to scientists working in the field, but areas of challenge and opportunity are highlighted that may stimulate new research at the chemistry-biology interface.