Background The attribution of personal relevance, i.e. relating internal and external stimuli to establish a sense of belonging, is a common phenomenon in daily life. Although previous research demonstrated a relationship between reward and personal relevance, their exact neuronal relationship including the impact of personality traits remains unclear. Methodology/Principal Findings Using functional magnetic resonance imaging, we applied an experimental paradigm that allowed us to explore the neural response evoked by reward and the attribution of personal relevance separately. We observed different brain regions previously reported to be active during reward and personal relevance, including the bilateral caudate nucleus and the pregenual anterior cingulate cortex (PACC). Additional analysis revealed activations in the right and left insula specific for the attribution of personal relevance. Furthermore, our results demonstrate a negative correlation between signal changes in both the PACC and the left anterior insula during the attribution of low personal relevance and the personality dimension novelty seeking. Conclusion/Significance While a set of subcortical and cortical regions including the PACC is commonly involved in reward and personal relevance, other regions like the bilateral anterior insula were recruited specifically during personal relevance. Based on our correlation between novelty seeking and signal changes in both regions during personal relevance, we assume that the neuronal response to personally relevant stimuli is dependent on the personality trait novelty seeking.