Corticotropin-releasing factor (CRF) is both a major regulator of the hypothalamo-pituitary-adrenal (HPA) axis and the activity of the autonomic nervous system. Besides, it exerts numerous effects on other physiological functions such as appetite control, motor and cognitive behavior and immune function. The basis for these effects is constituted by its distribution in hypothalamic and extra-hypothalamic brain areas, the latter being represented by limbic structures such as the central nucleus of the amygdala or by brain stem neurons such as the locus coeruleus (LC) or nucleus of the solitary tract (NTS). The effects of CRF are mediated through recently described CRF-receptor subtypes, whose molecular biology, biochemistry and pharmacological regulation are discussed in detail. In the second part of this review, we will focus on the physiology of CRF-systems in the brain, with a particular emphasis on cardiovascular regulation, respiration, appetite control and stress-related behavior. Finally, the role of the locus coeruleus in the control of CRF-mediated behavioral activities is discussed. The interaction of noradrenergic and CRF-neurons clearly implies that CRF appears to directly activate LC neurons in a stressful situation, thus ultimately coordinating the bodily response to a stressful stimulus.