The Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association, currently in its fourth edition and considered the reference for the characterization and diagnosis of mental disorders, has undergone various developments since its inception in the mid-twentieth century. With the fifth edition of the DSM presently in field trials for release in 2013, there is renewed discussion and debate over the extent of its relative successes - and shortcomings - at iteratively incorporating scientific evidence on the often ambiguous nature (...) and etiology of mental illness. Given the power that the DSM has exerted both within psychiatry and society at large, this essay seeks to analyze variations in content and context of various editions of the DSM, address contributory influences and repercussion of such variations on the evolving landscape of psychiatry as discipline and practice over the past sixty years. Specifically, we document major modifications in the definition, characterization, and classification of mental disorders throughout successive editions of the DSM, in light of shifting trends in the conceptualization of psychopathology within evolving schools of thought in psychiatry, and in the context of progress in behavioral and psychopharmacological therapeutics over time. We touch upon the social, political, and financial environments in which these changes took places, address the significance of these changes with respect to the legitimacy (and legitimization) of what constitutes mental illness and health, and examine the impact and implications of these changes on psychiatric practice, research, and teaching. We argue that problematic issues in psychiatry, arguably reflecting the large-scale adoption of the DSM, may be linked to difficulties in formulating a standardized nosology of psychopathology. In this light, we highlight 1) issues relating to attempts to align the DSM with the medical model, with regard to increasing specificity in the characterization of discrete mental disease entities and the incorporation of neurogenetic, neurochemical and neuroimaging data in its nosological framework; 2) controversies surrounding the medicalization of cognition, emotion, and behavior, and the interpretation of subjective variables as 'normal' or 'abnormal' in the context of society and culture; and 3) what constitutes treatment, enablement, or enhancement - and what metrics, guidelines, and policies may need to be established to clarify such criteria. (shrink)