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Publisher Summary Mechanism-based enzyme inactivation is now a mature field of endeavor in which basic chemical principles are applied to the construction of enzyme inhibitors. The design of mechanism-based inactivating agents is greatly facilitated by detailed knowledge of the catalytic mechanism of the target enzyme, but the chemical logic that links the catalytic mechanism to inactivation also makes such agents powerful probes of the catalytic process. A few general approaches, all of which involve introduction of a latent reactive functionality into a carrier structure that is recognized and processed by the enzyme, have emerged for the design of mechanism-based inactivating agents. The most common of these approaches is the insertion of a function that is catalytically converted to a Michael acceptor, but the full breadth of organic reactive species, including cations, anions, free radicals, and neutral species such as benzyne and cyclobutadiene, have been pressed into service in the design of mechanism-based inactivating agents.