Complex psychiatric disorders, such as schizophrenia, arise from a combination of genetic, developmental, environmental and social factors. These vulnerabilities can be mitigated by adaptive factors in each of these domains engendering resilience. Modeling resilience in mice using transgenic approaches offers a direct path to intervention, as resilience mutations point directly to therapeutic targets. As prototypes for this approach, we discuss the three mouse models of schizophrenia resilience, all based on modulating glutamatergic synaptic transmission. This motivates the broader development of schizophrenia resilience mouse models independent of specific pathophysiological hypotheses as a strategy for drug discovery. Three guiding validation criteria are presented. A resilience-oriented approach should identify pharmacologically tractable targets and in turn offer new insights into pathophysiological mechanisms.