The study of the brain mechanisms underlying vulnerability to disorder has fallen outside of the primary spotlight. This chapter argues that work of this nature is critical to bridging studies in healthy volunteer and patient groups and to identifying the pathways through which risk to affective illness is conferred. Studies of the brain basis of vulnerability to affective disorder can be categorized according to the measure used to assess individual differences in trait affective style. Studies on the brain basis of vulnerability to affective disorder falling within these categories have used measures of trait anxiety or neuroticism. The chapter considers some findings that explain the brain basis of trait vulnerability to affective disorder. It reviews the increased integration of the stress, epigenetics, and functional genomics literature. The chapter outlines causal trajectories underlying observed individual differences in affective style, disorder-related symptomatology, processing of emotionally salient stimuli, and associated brain function.