Release of acetylcholine (ACh) into the neocortex and hippocampus profoundly alters cellular excitability, network synchronization and behavioral state. Despite its diverse cellular and synaptic targets, the actions of ACh can be highly specific, altering the excitability of distinct inhibitory and excitatory cell types. This review presents evidence for the selectivity of cholinergic neuromodulation in GABAergic interneurons and identifies emerging parallels between the neocortex and hippocampus. In light of growing evidence that neuromodulatory specializations relate to neurochemical identity, I propose that differential engagement of neurochemically distinct interneuron subtypes is a unifying principle by which ACh orchestrates the flow of sensory information in the neocortex and hippocampus.