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Two classification systems are now at the forefront of clinical psychiatric research: (1) Diagnostic and Statistical Manual, Fifth Edition and (2) the National Institutes of Mental Health Research Domain Criteria. Herein, we propose that these two classification systems are complementary rather than mutually exclusive, and when combined provide important information for understanding aspects of the pathophysiology related to Generalized Anxiety Disorder (GAD). The neurobiological literature for GAD and one relevant research domain criteria component, sustained threat, are reviewed from multiple units of analysis (genetic, neuroimaging, neuroendocrine, and psychophysiological). It is hypothesized that generating a comprehensive, biologically based understanding of the relationship between GAD, sustained threat, and the measureable units of analysis will provide information critical to design the most effective treatments.