Stimuli that are interpreted by the brain as extreme or threatening, regardless of their modality, elicit an immediate stereotypic response characterized by enhanced cognition, affective immobility, vigilance, autonomic arousal and a global catabolic state. The brain's ability to mobilize this so-called stress response is paralleled by activation of corticotropin-releasing hormone (CRH) in several nuclei, including the hypothalamus, amygdala and locus ceruleus, and stimulation of the locus ceruleus norepinephrine (LC/NE) system in the brain stem. These systems perpetuate one another, interact with several other transmitter systems in the brain and directly activate the hypothalamic-pituitary-adrenal (HPA) axis and the three components of the autonomic nervous system, namely the sympatho-adrenal, the cranio-sacral parasympathetic and the enteric nervous systems. The widespread body system responses to stress are discussed, and the implications of aberrant stress system activity on physical and mental health are outlined. Moreover, the promise of nonpeptide CRH type-1 receptor antagonists to directly target the stress system in the brain is highlighted.