Organisms exposed to challenging stimuli that alter the status quo inside or outside of the body are required for survival purposes to generate appropriate coping responses that counteract departures from homeostasis. Identification of an executive control mechanism within the brain capable of coordinating the multitude of endocrine, physiological, and functional coping responses has high utility for understanding the response of the organism to stressor exposure under normal or pathological conditions. The corticotropin-releasing factor (CRF)/urocortin family of neuropeptides and receptors constitutes an affective regulatory system due to the integral role it plays in controlling neural substrates of arousal, emotionality, and aversive processes. In particular, available evidence from pharmacological intervention in multiple species and phenotyping of mutant mice shows that CRF/urocortin systems mediate motor and psychic activation, stimulus avoidance, and threat recognition responses to aversive stimulus exposure. It is suggested that affective regulation is exerted by CRF/urocortin systems within the brain based upon the sensitivity of local brain sites to CRF/urocortin ligand administration and the appearance of hypothalamo-pituitary-adrenocortical activation following stressor exposure. Moreover, these same stress neuropeptides may constitute a mechanism for learning to avoid noxious stimuli by facilitating the formation of so-called emotional memories. A conceptual framework is provided for extrapolation of animal model findings to humans and for viewing CRF/urocortin activation as a continuum measure linking normal and pathological states.