The expanding number of targeted covalent small molecule inhibitors in clinical development increases the importance of identification and quantitation of on- and off-target engagement for these molecules in order to better understand the level of target binding and inhibition and potential side effects. Here we describe the optimization of a click chemistry-based chemoproteomic approach, to study the target engagement of covalent molecules. Using the BTK inhibitor ibrutinib as a casa study, we aim to characterize its mechanistic profile in cell-systems.