Emotion Regulation (ER) includes different mechanisms aiming at volitionally modulating emotional responses, including cognitive re-evaluation (re-appraisal; REAP) or inhibition of emotion expression and behavior (expressive suppression; ESUP). However, despite the importance of these ER strategies, previous functional magnetic resonance imaging (fMRI) studies have not sufficiently disentangled the specific neural impact of REAP versus ESUP on brain responses to different kinds of emotion-eliciting events. Moreover, although different effects have been reported for stimulus valence (positive vs. negative), no study has systematically investigated how ER may change emotional processing as a function of particular stimulus content variables (i.e., social vs. nonsocial). Our fMRI study directly compared brain activation to visual scenes during the use of different ER strategies, relative to a "natural" viewing condition, but also examined the effects of ER as a function of the social versus nonsocial content of scenes, in addition to their negative versus positive valence (by manipulating these factors orthogonally in a 2×2 factorial design). Our data revealed that several prefrontal cortical areas were differentially recruited during either REAP or ESUP, independent of the valence and content of images. In addition, selective modulations by either REAP or ESUP were found depending on the negative valence of scenes (medial fusiform gyrus, anterior insula, dmPFC), and on their nonsocial (middle insula) or social (bilateral amygdala, mPFC, posterior cingulate) significance. Furthermore, we observed a significant lateralization in the amygdala for the effect of the two different ER strategies, with a predominant modulation by REAP on the left side but by ESUP on the right side. Taken together, these results do not only highlight the distributed nature of neural changes induced by ER, but also reveal the specific impact of different strategies (REAP or ESUP), and the specific sites implicated by different dimensions of emotional information (social or negative).