Covalent drugs feature a reactive functional group that establishes covalent bonds with protein targets, augmenting binding affinity beyond non-covalent interactions. Many early covalent drugs were discovered serendipitously and are known to bind active sites to inhibit enzymatic activity (e.g. Aspirin). Over the last three decades, there has been growing interest in the rational design of covalent drugs, with a focus on targeting certain amino acids to enhance selectivity. The prolonged engagement of target proteins by covalent drugs offers unique pharmacodynamic profiles. Despite concerns regarding reactivity, the potential advantages of covalent drugs have motivated medicinal chemists to explore this domain. Through careful optimization balancing reactivity, selectivity, and potency, several safe and efficacious drugs have been developed (e.g. ritlecitinib, ibrutinib and Osimertinib). By combining the power of mass spectrometry to decipher the mechanism of action of study drugs with nanoBret proximity assay, we were able to assess the specificity and affinity of compounds to the target proteins in a biochemical and cellular context.