Anxiety disorders constitute the most common group of psychiatric disorders with a lifetime prevalence of 14.5–33.7%. Despite efficacious pharmacological and psychological treatments, first line treatment is often not effective, and development of new therapies is needed. One area of interest is the orexin system, a neurotransmitter system centred in the lateral hypothalamus with widespread projections throughout the brain, including to several key areas involved in the modulation of fear and anxiety. In this article, we summarise findings from pre-clinical and clinical investigations of the potential role of the orexin system in the neurobiology of fear and anxiety. Pre-clinical studies in rodents generally indicate that orexin signalling promotes fear and anxiety-related behaviour, particularly in response to aversive stimuli. Orexin signalling in the amygdala, bed nucleus of the stria terminalis, paraventricular nucleus of thalamus, locus coeruleus and prefrontal cortex has been specifically implicated. Human studies are limited, with some evidence that orexin receptor antagonists are anxiolytic in experimental medicine models of anxiety, some indications from clinical populations of altered orexin signalling, and a molecular genetic study associating a non-synonymous variant in the orexin 1 receptor (HCRTR1) with panic disorder and agoraphobia. Given this emerging body of evidence, further human studies are required to fully assess the orexin system as a potential novel anxiolytic target.