The impact of cysteine-targeting covalent modifiers has spurred interest in the development of complementary 'beyond-cysteine' approaches to target additional amino acid residues and thus expand applicability across the proteome (Fig. ). Sulfur(VI) fluorides (SFs), have emerged as useful electrophiles for this application, targeting multiple nucleophilic amino acid residues, including: lysine, tyrosine, and serine. The prevalence of these residues in almost all protein pockets makes SFs promising functional groups for the development of covalent inhibitors for proteins, and expansion of the liganded proteome. Recently, several SF-containing modulators have been reported, which enabled covalent modification of protein pockets without targeting a cysteine. Examples include 'XO44' for broad-spectrum kinase profiling, various SF-containing ligands for targeting G protein-coupled receptors including the human adenosine A3 receptor, and 'EM12-SO2F'/'EM12-FS' which modulate cereblon. These were developed by structure-based, rational installation of the SF group on optimised non-covalent scaffolds. The development of complementary 'bottom-up' approaches will be useful for discovering ligands for targets that have low tractability to non-covalent ligands. Reactive fragment screening has emerged as a useful strategy for the discovery of chemical probes for protein targets of interest. These approaches couple the utility of fragments in enabling the efficient coverage of chemical space, with a reactive functionality that traps weak protein-ligand interactions to improve binding, and enable robust detection by intact protein liquid chromatography-mass spectrometry (LC-MS) (Fig. ). Covalent capture provides access to a suite of follow-up studies that further characterise the interaction, including determination of the site(s) of binding, measurement of kinetic parameters, and assessment of in-cell target engagement. To date, the approach has been limited to cysteine-targeting covalent inhibitors for challenging targets, including HOIP, and KRAS G12C , which led to the discovery of the FDA approved therapeutic AMG 510. Chemistries that enable the screening of electrophilic libraries to target alternative nucleophilic residues would greatly expand the number of proteins that are amenable to reactive fragment screening technologies.