This paper is focusing on a rather neglected issue that concerns both aspects of philosophy and neurobiology in relation to the concept of intentionality. Intentionality is concerned with the ‘directedness’ or ‘aboutness’ of mental phenomena towards an object. Despite the fact that in philosophy both concepts of aboutness and directedness are conceptually identical with intentionality, a careful neuroscientific approach can demonstrate that these two phenomena represent two distinct conceptual and neurobiological aspects of intentionality with complementary functions. We described the interaction between a series of intentionality and pathogenetic psychobiological factors, the corresponding brain topography, and the resulting clinical manifestation and psychopathology. A permanent failure of intentionality dominates in psychosis, which includes an inappropriateness of the intentional object or connection, from the outset, or even from the prodromal phase of the disorder. Affective disorders may result from imprecise interoceptive prediction error signals, due to a confused identification of the intentional object. In suicidal patients there is an emotional intentionality failure, characterized by an absence of intentional object or a loss of conscious access to normal intentional objects. We may model an ‘intentional system’ as a higher order system, with a monitoring and regulatory role attributed to the brain and behavior. Also, we may consider mental disorders as the result of a radical disruption of intentionality, due to an inappropriateness or lack of the intentional object or due to an inappropriate connection in some points of the suggested brain pathways of intentionality.