Orexin or Hypocretin is a neuropeptide, produced in the lateral hypothalamic neurons. The neurons send their projections throughout the brain and apply region-specific modulatory functions. Two discovered primary functions of orexin are the involvement of orexin in food intake and sleep regulation. The regulation of neurobiological mechanisms involved in the stress response is one of the most important orexin functions. Orexin terminals and receptors are distributed in many memory and stress-related areas such as the hippocampus. Stress, as a homeostatic challenge, leads to the malfunction of learning and memory processes. Orexin affects the behavioral and physiologic signs of stress by enhancing the activity of the paraventricular nucleus and secretion of corticotropin-releasing hormone, which in turn reinforces the function of orexin neurons, as a reciprocal circuitry. This mutual activation establishes a kind of positive feedback mechanism and a form of stress memory in the circuitry. Further studies are necessary for a better understanding of central and peripheral orexin functions and these results may help treat diseases especially anxiety disorders. We will review the recent findings regarding orexin and its role in stress response.