This research examined the hypothesis that reduced posterior right hemisphere activity interferes with the regulation of emotions and behavior in response to stress, creating vulnerability to depression. Consistent with a diathesis-stress model, we predicted that youth with a reduced posterior right hemisphere bias in emotional processing would engage in less adaptive responses to stress, which would be associated with depressive symptoms in those who reported the recent experience of high, but not low, levels of stress. Participants were 510 4th through 8th graders who completed the Chimeric Faces Task and measures of responses to stress and depressive symptoms. Results supported the idea that responses to stress account for the association between reduced posterior right hemisphere activity and depressive symptoms in youth who report high, but not low, levels of stress. This study provides insight into one process through which reduced posterior right hemisphere activity may confer vulnerability to depressive symptoms, and implicates responses to stress as a target for intervention.