Ground-state destabilization of the N−C(O) linkage represents a powerful tool to functionalize the historically inert amide bond. This burgeoning reaction manifold relies on the availability of amide bond precursors that participate in weakening of the n N → π* C=O conjugation through N−C twisting, N pyramidalization, and n N electronic delocalization. Since 2015, acyl N−C amide bond activation through ground-state destabilization of the amide bond has been achieved by transition-metal-catalyzed oxidative addition of the N−C(O) bond, generation of acyl radicals, and transition-metal-free acyl addition. This Perspective summarizes contributions of our laboratory in the development of new ground-state-destabilized amide precursors enabled by twist and electronic activation of the amide bond and synthetic utility of ground-state-destabilized amides in cross-coupling reactions and acyl addition reactions. The use of ground-state-destabilized amides as electrophiles enables a plethora of previously unknown transformations of the amide bond, such as acyl coupling, decarbonylative coupling, radical coupling, and transition-metal-free coupling to forge new