The hypocretins (also know as orexins) are two neuropeptides now commonly described as critical components for maintaining and regulating the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. New data indicate that the corticotrophin-releasing factor (CRF) peptidergic system directly innervates hypocretin-expressing neurons. CRF depolarizes hypocretin neurons, and this effect is blocked by a CRF-R1 antagonist. Furthermore, activation of hypocretinergic neurons by stress is impaired in CRF-R1 knockout mice. These data suggest that CRF-R1 receptor mediates the stress-induced activation of the hypocretinergic system. A significant amount of evidence also indicates that hypocretin cells connect reciprocally to the CRF system. We propose that upon stressor stimuli, CRF activates the hypocretin system, which relays these signals to brain stem nuclei involved in the modulation of arousal as well as to the extended amygdala, a structure involved in the negative motivational state that drives addiction.