Cholinergic signaling in the cortex involves fast or transient signaling as well as a relatively slower neuromodulatory component. These two components of cholinergic activity mediate separate yet interacting aspects of cue detection and attentional control. The transient component appears to support the activation of cue-associated task or response sets, whereas the slower modulatory component stabilizes task-set and context representations, therefore potentially facilitating top–down control. Evidence from humans expressing genetic variants of the choline transporter as well as from patients with degenerating cholinergic systems supports the hypothesis that attentional control capacities depend on levels of cholinergic neuromodulation. Deficits in cholinergic–attentional control impact diverse cognitive functions, including timing, working memory, and complex movement control.