A strategy for activity-based enzyme detection using a novel enamide-based chemical strategy is described. Enzymatic cleavage of an amide bond results in the formation of an aldehyde. The interaction of this aldehyde with proteins increases retention in cells that express the enzyme. Proof of concept for this enamide-based strategy is demonstrated by detecting histone deacetylase (HDAC) activity in HeLa cells. The modular design of this strategy makes it amenable to in vitro and in vivo detection.