Stress related diseases such as depression and anxiety have a high degree of co morbidity, and represent one of the greatest therapeutic challenges for the twenty-first century. The present chapter will summarize existing rodent models for research in psychiatry, mimicking depression- and anxiety-related diseases. In particular we will highlight the use of selective breeding of rodents for extremes in stress-related behavior. We will summarize major behavioral, neuroendocrine and neuronal parameters, and pharmacological interventions, assessed in great detail in two rat model systems: The Flinders Sensitive and Flinders Resistant Line rats (FSL/FRL model), and rats selectively bred for high (HAB) or low (LAB) anxiety related behavior (HAB/LAB model). Selectively bred rodents also provide an excellent tool in order to study gene and environment interactions. Although it is generally accepted that genes and environmental factors determine the etiology of mental disorders, precise information is limited: How rigid is the genetic disposition? How do genetic, prenatal and postnatal influences interact to shape adult disease? Does the genetic predisposition determine the vulnerability to prenatal and postnatal or adult stressors? In combination with modern neurobiological methods, these models are important to elucidate the etiology and pathophysiology of anxiety and affective disorders, and to assist in the development of new treatment paradigms.