The self is central in our mental life and disturbances of the self-figure most prominently in psychopathological symptoms. The cortical midline structures (CMS) have been associated with self-related processing and its changes in schizophrenia, depression and other psychiatric disorders. However, the exact neuronal mechanisms underlying self-related processing in CMS and its changes in psychiatric disorders remain unclear. Especially the neural overlap between high resting state activity levels and self-related processing in CMS is rather puzzling. I present recent data on the rest-self overlap in healthy subjects showing that resting state activity in CMS can predict self-relatedness. The implications for psychological symptoms as in depression and schizophrenia are pointed out.