Depression is a devastating mental disorder with an increasing impact throughout the world, whereas the efficacy of currently available pharmacological treatment is still limited. Growing evidence from preclinical and clinical studies suggests that orexins (neuropeptides that are also known as hypocretins) and their receptors are involved in the physiopathology of depression. Indeed, the orexinergic system regulates functions that are disturbed in depressive states such as sleep, reward system, feeding behavior, the stress response and monoaminergic neurotransmission. Nevertheless, the precise role of orexins in behavioral and neurophysiological impairments observed in depression is still unclear. Both hypoactivity and hyperactivity of orexin signaling pathways have been found to be associated with depression. These discrepancies in the literature prompted the necessity for additional investigations, as the orexinergic system appears to be a promising target to treat the symptoms of depression. This assumption is underlined by recent data suggesting that pharmacological blockade of orexin receptors induces a robust antidepressant-like effect in an animal model of depression. Further preclinical and clinical studies are needed to progress the overall understanding of the orexinergic alterations in depression, which will eventually translate preliminary observations into real therapeutic potential. The aim of this paper is to provide an overview of human and animal research dedicated to the study of the specific involvement of orexins in depression, and to propose a framework in which disturbances of the orexinergic system are regarded as an integral component of the etiology of depression.