The authors examined the effects of smoking expectancy on cue-reactivity among those motivated and those unmotivated to quit smoking using functional MRI. Cue-elicited activation was observed in the rostral prefrontal cortex (PFC) in smokers who expected to smoke within seconds, but not in those who expected to have to wait hours before having the chance to smoke, regardless of quitting motivation. For quitting-unmotivated smokers expecting to smoke, rostral PFC activation was strongly positively correlated with the activation of several areas previously linked to cue-reactivity, including the medial orbitofrontal cortex (OFC) and rostral anterior cingulate cortex (ACC). In contrast, there was a nonsignificant negative relationship between activation of the rostral PFC and activation of the medial OFC/rostral ACC in quitting-motivated smokers expecting to smoke. Results extend previous work examining the effects of smoking expectancy and highlight the utility of examining interregional covariation during cue exposure. Findings also suggest that investigators may need to pay close attention to the motivational contexts associated with their experiments when studying cue-reactivity, as these contexts can modulate not only responses to drug cues, but perhaps also the functional implications of observed activity.