Maintenance of homeostasis in the presence of real or perceived challenges requires numerous adaptive responses involving changes in the central nervous, immune and neuroendocrine systems. Both activation and termination of the behavioral, autonomic and adrenocortical stress responses are critical for adaptation and survival. Accumulating genetic and pharmacological studies support an important role for the brain Urocortins / corticotropin releasing factor receptor type 2 (CRFR2) system in mediating behavioral and physiological responses to diverse stressors. This system may be particularly important in situations where an organism must mobilize not only the hypothalamic-pituitary-adrenal system, but also the central nervous system in response to environmental challenge. Clearly, dysfunction in such a fundamental brain-activating system may be the key to a variety of pathophysiological conditions involving abnormal responses to stressors such as anxiety, affective and eating disorders. While CRFR2 and the triple Urocortin mutant mice show increased anxiety-like behaviors following challenge, the anxiety-related effects of administration of CRFR2 agonists and antagonists into the cerebral ventricles or into specific brain regions have been less consistent, with some evidence for brain site or ligand specificity. This lecture will summarize our recent findings using genetic and optogenetic experiments concerning the role of the central Urocrtins/CRFR2 system in the regulation of the central stress response.