The recent publication of the DSM-5 has been preceded and followed by a lively debate, in which recurring arguments have been that the manual, referred to as’the bible of psychiatry’, mislabels many people who are basically normal and that the diagnostic categories it contains are invalid, not being based on objective laboratory tests. We present data on the utilization of the ICD and DSM worldwide, showing that the DSM is used by only a minority of European psychiatrists in clinical settings. We highlight the gap between diagnostic systems and ordinary diagnostic practice, which should be addressed by future research and action. We discuss the need to assess systematically the pros and cons of the operational and prototype approaches to psychiatric diagnosis, with a special focus on their applicability in ordinary practice and clinical utility. We consider different views about what qualifies as mental disorder and how the boundary between pathology and normality should be fixed for each mental disorder. We review the role of laboratory tests as applied in medicine, emphasizing that most of them are probabilistic, not pathognomonic, markers of disease, and that their availability has not prevented some non-psychiatric conditions which are on a continuum with normality to become the subject of controversy as to the appropriate’threshold’ for the diagnosis. We summarize the promise and limitations of the Research Domain Criteria project, aiming to’transform psychiatric diagnosis’.