The hypocretins, also known as orexins, are neuropeptides produced in a few thousand neurons in the lateral hypothalamus (LH). Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward and stress. In addition to being key regulators of arousal, these peptides have been shown to influence many diverse functions and consummatory behaviors. They have recently been described as a component of the circuitries that mediate the hypothalamic response to acute stress, notably by connecting to the extended amygdala that includes the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala, but their role in addiction-related behaviors remains largely unexplored. In the present study, we show that intracerebroventricular (ICV) infusions of hypocretin-1 (1, 2.5 and 5) leads to a dosedependent reinstatement of previously extinguished cocaine-seeking behavior without, however, altering cocaine intake (0.25 mg/infusion) in rats. In parallel, hypocretin-1 (5, ICV) dramatically elevated intracranial self-stimulation (ICSS) thresholds, indicating that hypocretin-1 negatively regulates the activity of brain reward circuitries. Hypocretininduced reinstatement of cocaine-seeking was prevented by simultaneous blockade of noradrenergic and corticotropin releasing factor systems, but not by blockade of either system alone, suggesting that Hcrt-1 reinstated drug seeking though induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist, SB 334867, blocked footshock-induced reinstatement of previously extinguished cocaine seeking behavior. Overall, these data suggest that Hypocretin-1 does not regulate the primary reinforcing effects of cocaine but may play a key role in the circuitry that underlies vulnerability to relapse, probably by driving drug-seeking through induction of a negative affective state due to the activation of stress pathways in the brain. This system may therefore represent a new target to prevent relapse for drug-seeking during protracted abstinence.