Covalent drugs offer high potency and prolonged target engagement; however, the off- target reactivity often raise concerns due to their irreversible nature. This study aims to systematically elucidate the relationship between warhead reactivity and proteome-wide selectivity to guide rational covalent drug design. A panel of covalent probes bearing diverse electrophilic warheads, including acrylamide, sulfonyl fluoride, and fluorosulfate, were synthesized and evaluated using activity-based protein profiling (ABPP). Initial results in HEK293 cells revealed that acrylamide and sulfonyl fluoride exhibit higher levels of off-target protein labeling compared to fluorosulfate-based warheads. Together, these studies establish a proteome- wide framework for evaluating covalent warheads and provide design principles for next- generation covalent therapeutics with improved selectivity and controlled reactivity.