Human genetics is providing much needed clues to mechanisms underlying neuropsychiatric disorders. Highly penetrant copy number variants (CNVs) were among the first genetic variants confidently associated with schizophrenia and autism spectrum disorders (ASDs). Despite their structural complexity, the high penetrance of CNVs associated with neuropsychiatric disorders suggested utility for construction of cellular and animal models. Human cellular models that carry disease associated alleles have the advantage of human genetic backgrounds against which to study the effects of CNVs. However, investigation of the effects of disease-associated alleles on the structure and function of living brains requires genome engineering of model organisms or introduction of genetic material into their brains by viral vectors. Here I focus on the translational utility of transgenic mice that carry models of human neuropsychiatric CNVs, while recognizing their limitations as veridical models of complex human brain disorders. In order to improve translational utility and avoid the intellectual cul-de-sacs that often bedevil interpretation of neuropsychiatric disease models, I conclude with a 'draft' proposal to replace current concepts of construct and face validity with more nuanced and contextually relevant judgments. Copyright © 2021 The Author. Published by Elsevier Ltd.. All rights reserved.