The use of electrophilic fragment libraries has emerged within chemical biology as a powerful approach for the identification of fragment-protein interactions. Electrophilic fragments covalently modify the protein, facilitating the use of intact protein liquid chromatography-mass spectrometry (LC-MS) for rapid and robust screening of libraries (~10 3 compounds) to identify binders. Covalent fragments that target cysteine residues have been identified and successfully optimised to cell-active tool compounds for proteins including e.g. HOIP and KRas. A limitation of these libraries is that a cysteine residue must be present in the vicinity of the binding site, and therefore, only a subset of proteins can be targeted. Strategies that enable reaction with a wider range of amino acid residues would expand the number of 'ligandable' pockets that can be pursued, and broaden the applicability of the approach.