Humans have long distinguished themselves from other living organisms. Therefore, to make use of animal models for neuropsychiatric disorders, it is important to acknowledge what has changed historically. Darwin argued that there was continuity in mind between humans and nonhuman species, and animal experimental psychologists and others have debated the existence of consciousness and mentality in animals ever since. Those trained in the associationist tradition sought to eliminate the concept of mind in favor of an empiricial, behavioral approach; others trained in the introspectionist tradition sought to include mental abilities as an integral part of comparative animal psychology. The waning of behaviorism and ascendance of cognitive psychology in the mid-twentieth century renewed interest in the notion of consciousness and mind in nonhuman organisms, particularly as they related to learning impairment and neurobehavioral disorders. Moreover, advances in molecular genetics and technology facilitated development of genetically modified mouse strains that could be used to examine cognitive deficits and psychopathology. However, genetic modifications to individual genes that produce behavioral dysfunction in the mouse have not always provided clear results. In part, this is likely due to the influence of genes in addition to the targeted gene, sometimes resulting in paradoxical effects. I also examine other issues created by the use of nonhuman models of human disorders, including: language, the effect of background genetic strains, genetic-environmental interactions, and the problems associated with the complex genetics needed to produce similarly complex behavioral phenotypes.