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Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high co-morbidity with other psychiatric and somatic deficits. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In addition, the reason why some individuals respond to SSRIs while others don’t are unknown. Here we begin to ask what the basis of treatment-resistance is, and propose new strategies to model this phenomenon in animals. We focus specifically on animal models that offer the appropriate framework to study treatment resistance with face, construct and predictive validity.