This paper first addresses the place of psychoanalysis in relation to certain other key bodies of knowledge: the thesis is that psychoanalysis is best understood as a highly specialized branch of human biology. Within this framework the main psychoanalytic ideas about depression in adults are described, giving particular attention to depression when it becomes a chronic, treatment-resistant state. Goldberg shows (pages 236–247 this issue) that the advances in genetics and neurobiology can be connected with those in developmental research (Murray & Hill, pages 185–199 & 200–212 this issue). This enables new light to be thrown upon the psychobiological diathesis which seems to underlie depression. This paper argues that an investigation of subjectivity and meaning is also necessary if our account of depression is to be complete. Without an understanding of meaningfulness, the function of the brain cannot be fully known. Finally, some clinical material shows why psychic reality has to be approached in its own terms.