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The National Institute of Mental Health is actively promoting Research Domain Criteria as a new model for the research on mental disorders. Research Domain Criteria approaches disorders through a matrix, linking units of analysis with domains, based on the assumption that psychopathology reflects abnormal connectivity in the brain. This review suggests that the Research Domain Criteria perspective is likely to fail to provide an adequate basis for clinical psychiatric theory and practice. First, it uses models from neuroscience that are insufficiently developed. Second, it is based on the premise that mental phenomena and mental disorders can be reduced to neural activity, without consideration of cognition, experience, and social interaction. Third, it downplays psychosocial factors in psychopathology and treatment. Research Domain Criteria may therefore prove inadequate for providing a neuroscientific basis for psychiatric nosology and treatment and needs to be supplemented with a broader view that incorporates insights from social sciences, psychology, and phenomenology.