fMRI was used to determine whether prefrontal regions play a predominant role in imposing an attentional 'set' that drives selection of task-relevant information. While monitoring for an atypical item, individuals viewed Stroop stimuli that were either colored words or colored objects. Attentional demands were varied, being greater when the stimuli contained two distinct and incongruent sources of information about the task-relevant attribute (e.g., when attending to color, seeing the word 'blue' in red ink) as compared to only one source (e.g., seeing the word 'late' in red ink). Prefrontal but not anterior cingulate regions exhibited greater activation on incongruent than neutral trials, suggesting that prefrontal cortex has a major role in imposing an attentional 'set'. In addition, we found that prefrontal activation is most likely to occur when that attentional set is difficult to impose.