Rejection sensitivity (RS) is the tendency to anxiously expect, readily perceive, and intensely react to rejection. This study used functional magnetic resonance imaging to explore whether individual differences in RS are mediated by differential recruitment of brain regions involved in emotional appraisal and/or cognitive control. High and low RS participants were scanned while viewing either representational paintings depicting themes of rejection and acceptance or nonrepresentational control paintings matched for positive or negative valence, arousal and interest level. Across all participants, rejection versus acceptance images activated regions of the brain involved in processing affective stimuli (posterior cingulate, insula), and cognitive control (dorsal anterior cingulate cortex; medial frontal cortex). Low and high RS individuals' responses to rejection versus acceptance images were not, however, identical. Low RS individuals displayed significantly more activity in left inferior and right dorsal frontal regions, and activity in these areas correlated negatively with participants' self-report distress ratings. In addition, control analyses revealed no effect of viewing negative versus positive images in any of the areas described above, suggesting that the aforementioned activations were involved in rejection-relevant processing rather than processing negatively valenced stimuli per se. Taken together, these findings suggest that responses in regions traditionally implicated in emotional processing and cognitive control are sensitive to rejection stimuli irrespective of RS, but that low RS individuals may activate prefrontal structures to regulate distress associated with viewing such images.