Orexin-A and orexin-B are two peptides derived by proteolytic cleavage from a 130 amino acid precursor prepro-orexin, which recently were isolated from the rat hypothalamus. Orexin-A is fully conserved across mammalian species, whilst rat and human orexin-B differ by 2 amino acids. These peptides bind to two G(q)-coupled receptors, termed OX(1) and OX(2). The receptors are 64% homologous and highly conserved across species. Orexin-A is equipotent at OX(1) and OX(2), whilst orexin-B displays moderate ( approximately 10-fold) selectivity for OX(2). Prepro-orexin is found in the hypothalamus and, to a markedly lesser extent, the testes, adrenals, and myenteric plexus. However, orexin-A and orexin-B are found throughout the CNS, due to extrahypothalamic projections, as well as in the adrenals and small intestine. OX(1) is expressed mainly in the hypothalamus and locus coeruleus, as well as other brain regions and the spinal cord. OX(2) is expressed in the hypothalamus, cortex, spinal cord, and a few discrete brain nuclei. Both receptors are also expressed in the gut. The orexins modulate feeding behaviour and energy homeostasis, as well as associated drinking behaviours, and also regulate the sleep-wake cycle. Moreover, disruption of prepro-peptide expression or mutations in the gene encoding OX(2) result in a narcoleptic phenotye in various animal models, whilst several clinical studies have linked disruption of the orexin system to narcolepsy in humans. The orexins also have cardiovascular and neuroendocrine effects. This review further details the pharmacology and localisation of these peptides and summarises the evidence for their role in the physiology outlined above.