We argue that many similar findings observed in cognitive, affective, and social neuroimaging research may compose larger processes central to generating self-relevance. In support of this, recent findings from these research domains were reviewed to identify common systemic activation patterns. Superimposition of these patterns revealed evidence for large-scale supramodal processes, which are argued to mediate appraisal of self-relevant content irrespective of specific stimulus types (e.g. words, pictures) and task domains (e.g. induction of reward, fear, pain, etc.). Furthermore, we distinguish between two top-down sub-systems involved in appraisal of self-relevance, one that orients pre-attentive biasing information (e.g. anticipatory or mnemonic) to salient or explicitly self-relevant phenomena, and another that engages introspective processes (e.g. self-reflection, evaluation, recollection) either in conjunction with or independent of the former system. Based on aggregate patterns of activation derived from the reviewed studies, processes in a ventral medial prefrontal cortex (MPFC)-subcortical network appear to track with the former pathway, and processes in a dorsal MPFC-cortical-subcortical network with the latter. As a whole, the purpose of this framework is to re-conceive the functionality of these systems in terms of supramodal processes that more directly reflect the influences of relevance to the self.