Targeted modification of endogenous proteins without genetic manipulation of protein expression machinery has a range of applications from chemical biology to drug discovery. Despite being demonstrated to be effective in various applications, target-specific protein labeling using ligand-directed strategies is limited by stringent amino acid selectivity. Here, we present highly reactive ligand-directed triggerable Michael acceptors (LD-TMAcs) that feature rapid protein labeling. Unlike previous approaches, the unique reactivity of LD-TMAcs enables multiple modifications on a single target protein, effectively mapping the ligand binding site. This capability is attributed to the tunable reactivity of TMAcs that enable the labeling of several amino acid functionalities via a binding-induced increase in local concentration while remaining fully dormant in the absence of protein binding. We demonstrate the target selectivity of these molecules in cell lysates using carbonic anhydrase as the model protein. Furthermore, we demonstrate the utility of this method by selectively labeling membrane-bound carbonic anhydrase XII in live cells. We envision that the unique features of LD-TMAcs will find use in target identification, investigation of binding/allosteric sites, and studying membrane proteins.