Hypocretins 1 and 2 (Hcrt1 and Hcrt2) are hypothalamic neuropeptides derived from a single precursor molecule by proteolytic processing. This chapter reports functional information on the receptors for the two peptides: the orexin-1 receptor (OX1R) was shown to preferentially bind orexin-A over orexin-B. Afferents to Hcrt neurons have been identified using two different methodologies: conventional retrograde tracing confirmed by anterograde tracing in rats and retrograde tracing using a genetically encoded tracer in mice. The projections of the Hcrt neurons are widely distributed in the brain and spinal cord. The Hcrt peptides have been reported as excitatory, eliciting depolarization and/or increased spike frequency. The implication of the Hcrt system in narcoleptic dog and mouse models led to the discovery of the likely cause of human narcolepsy. An abnormality in Hcrt neurotransmission in narcoleptic humans was suggested by undetectable levels of Hcrt1 in cerebrospinal fluid (CSF) from seven of nine narcoleptic patients.