The problem of the self has been of increasing interest in recent neuroscience. Brain imaging studies have raised the question of whether neural activity in cortical midline regions is self-specific and whether self-specific activity is related to resting state activity (RSA). A quantitative meta-analysis that included 87 studies, representing 1433 participants, was conducted to discuss these questions. First, the specificity of the self (e.g. hearing one's own name, seeing one's own face) was tested and compared across familiar (using stimuli from personally known people) and other (non-self-non-familiar, i.e. strangers and widely-known figures) conditions. Second, the relationship between the self and resting state activity, as reflected by the default-mode network (DMN), was tested. The results indicated that the perigenual anterior cingulate cortex (PACC) is specifically involved in self-processing when compared to familiarity, other, and task/stimulus effects. On the contrary, other midline regions, i.e., medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) were functionally unspecific as they were recruited during the processing of both self-specific and familiar stimuli. Finally, the PACC was recruited during self-specific stimuli and this activity overlapped with DMN activity during resting state, thus distinguishing the self-related processing from both that of the familiar and other conditions. Taken together, our data suggest that our sense of self may result from a specific kind of interaction between resting state activity and stimulus-induced activity, i.e., rest-stimulus interaction, within the midline regions.