Cognitive-motivational styles describe predominant patterns of processing or biases that broadly influence human cognition and performance. Here we focus on the impact of cognitive-motivational styles on the response to cues predicting the availability of food or addictive drugs. An individual may preferably conduct an analysis of the motivational significance of reward cues, with the result that such cues per se are perceived as rewarding and worth approaching and working for. Alternatively, a propensity for a “cold” analysis of the behavioral utility of a reward cue may yield search behavior for food or drugs but not involve cue approach. Animal models for studying the neuronal mechanisms mediating such styles have originated from research concerning behavioral indices that predict differential vulnerability to addiction-like behaviors. Rats classified as sign- or goal-trackers (STs, GTs) were found to have opposed attentional biases (bottom-up or cue-driven attention vs. top-down or goal-driven attentional control) that are mediated primarily via relatively unresponsive versus elevated levels of cholinergic neuromodulation in the cortex. The capacity for cholinergic neuromodulation in STs is limited by a neuronal choline transporter (CHT) that fails to support increases in cholinergic activity. Moreover, in contrast to STs, the frontal dopamine system in GTs does not respond to the presence of drug cues and, thus, biases against cue-oriented behavior. The opponent cognitive-motivational styles that are indexed by sign- and goal-tracking bestow different cognitive–behavioral vulnerabilities that may contribute to the manifestation of a wide range of neuropsychiatric disorders.