The categorical view of mental illness, which implies the existence of discrete neuropsychiatric disorders that are distinguishable from each other as well as from the healthy state, is evolving into a more realistic “dimensional” view. The dimensional view explains neuropsychiatric symptoms in terms of natural phenotypical variance along certain independent dimensions that are continuous with “normal.” This view can account for the comorbidity and extensive symptom sharing that is observed among categorically defined disorders. Classic animal models of neuropsychiatric disorders—very much in line with the categorical model of psychopathology—explicitly or implicitly attempt to replicate the human disorder in the animal subject, and the validity of the model hinges on how closely the animal model match the human condition. As the conceptualization of mental illness shifts from categorical to dimensional, approaches to animal modeling of mental illness must also change. Dimensional approaches to animal modeling include the “domain interplay” approach proposed by Kalueff and colleagues (Kalueff et al., 2008a, Kalueff et al., 2008b, LaPorte et al., 2010), the “behavioral domain” approach proposed by Kas and colleagues (Kas et al., 2007, Kas et al., 2009, Kas et al., 2011). A common theme running through these newer ideas is that psychopathology represents dysfunction in specific cognitive, emotional, or behavioral domains (such as fear and stress responsiveness, motivation, hedonic capacity, and social interaction). These domains comprise adaptive responses and behaviors that are conserved among mammalian and nonmammalian species. Identifying the genetic and environmental factors associated with phenotypic variation within these domains should provide clues to understanding the etiology of neuropsychiatric disorders. Likewise, the “domain interplay” approach aims to identify factors that are associated with dysfunction in multiple domains and those that underlie the tendency for certain domain dysfunctions to co-occur. This chapter provides an overview of the natural history of the laboratory mouse and rat, emphasizing how domestication has altered some behavioral characteristics, while other behaviors have remained unchanged. An understanding of rodent behavior in natural conditions can provide new insights into laboratory rodent behavior and suggest alternative interpretations of the results that are obtained in standard behavioral tests. Factors responsible for individual differences in personality traits are likely to overlap with those that confer vulnerability to mental illness, so the study of individual differences in “animal personality” is highly relevant to understanding psychopathology. One basic stable personality trait, coping style, is strongly associated with behavioral responses in several tests that are relevant to modeling neuropsychiatric disorders. The proactive coping style is associated with decreased behavioral and cognitive flexibility, decreased immobility in the forced swim tests, susceptibility to learned helplessness, and susceptibility to developing stereotypies. The reactive coping style is associated with increased behavioral and cognitive flexibility, increased immobility in the forced swim test, and increased avoidance behavior in approach–avoidance test paradigms. Personality is formed through an interaction between genotype and environment. Some important environmental factors that can account for individual differences in behavioral traits are prenatal stress and intrauterine position (in the case of litter-bearing mammals), the mother–young interactions, the social status of the mother, and environmental enrichment. Finally, this chapter discusses which aspects of human mental illness probably do not have homologs in nonhuman animals; these include rumination, anxiety sensitivity, and metacognition. Nevertheless, a body of work indicates that the so-called “big-brained” mammals (great apes, elephants, and dolphins) might have human-like capacities for self-awareness, empathy, metacognition, and perhaps theory of mind.