Targeted covalent inhibitors (TCIs) form covalent bond with their target that requires tailored reactive functionalities identified as warheads. Here we present a versatile approach changing carboxamide functions with thioamides that transforms known warheads to softer electrophiles enhancing reactivity and specificity for covalent cysteine modification. Furthermore, the oxygen-sulfur (O-S) exchange led to the discovery of new electrophilic warhead chemotypes such as chloroethanethioamides and fluoroethanethioamides. The improved reactivity and specificity of thioamide warheads were demonstrated in comparative labelling experiments of carboxamide and thioamide ibrutinib analogues at BTK. Additionally, we synthesized and evaluated alkyne-tagged thioamide derivatives in chemoproteomic applications. In addition to the increased reactivity observed at the proteome level, the chloroethanethioamide probe preferentially labeled a different subset of the proteome compared to iodoacetamide. Our findings suggest that thioamide warheads are suitable for TCI development and chemical biology applications, offering alternative cysteine-specific chemotypes for future covalent probe design.