In this paper we consider two major issues: conceptual–experimental approaches to the self, and the neuroanatomical substrate of the self. We distinguish content- and processed-based concepts of the self that entail different experimental strategies, and anatomically, we investigate the concept of midline structures in further detail and present a novel view on the anatomy of an integrated subcortical–cortical midline system. Presenting meta-analytic evidence, we show that the anterior paralimbic, e.g. midline, regions do indeed seem to be specific for self-specific stimuli. (...) We conclude that future investigation of the self need to develop novel concepts that are more empirically plausible than those currently in use. Different concepts of self will require novel experimental designs that include, for example, the brain’s resting state activity as an independent variable. Modifications of both conceptual and anatomical dimensions will allow an empirically more plausible account of the relationship between brain and self. (shrink)