Data since 1980 demonstrate that the DSM-III model requires revisions in its assumptions and format. Problems inherent in the DSM-III model are considered and a paradigm shift toward a mixed categoricaldimensional classification system for DSM-V is recommended. This will reduce comorbidity, allow symptom weighting, introduce noncriterion symptoms, eliminate NOS categories, and provide new directions to biological researchers. We suggest reevaluating the threshold concept and use of quality-of-life assessment. A framework for such a revision is presented. Drawbacks to change include retraining of clinicians, administrative and policy changes, and possible reinterpretation of data collected under the DSM-III model. Nevertheless, clinicians and clinical researchers are ready for a diagnostic system that more accurately reflects the patients that they treat and study.The format and assumptions of the third edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-III , American Psychiatric Association, 1980), have served as a model for all successive editions. The third edition was considered a paradigm shift in nosology (Klerman, 1990), and data since 1980 demonstrate the need for a second paradigm shift. This article will raise issues regarding the assumptions underlying the DSM-III model and format by which psychopathology is presented: inadequate use of dimensions, the threshold concept, discontinuity with normality and subthreshold psychopathology, signs and symptoms and their weighting, comorbidity, and quality-of-life to complement psychosocial functioning. We also discuss some consequences of departing from nearly three decades of hegemony by the DSM-III model.Although space limits the inclusion of dozens of articles that would support the issues addressed, we provide examples of data from this large literature. Excepting one point, the theoretical underpinnings of psychopathology are not discussed. If the theory is supported by data, is heuristic, or is useful in treatment, DSM-V might include some specific etiological theories. Incorporation of evolution theory in DSM-V is discussed elsewhere (Bracha & Maser, 2008).