The lateral hypothalamic area (LHA) contains a large population of neurons that express the enzyme acetylcholinesterase (AChE), but are not themselves cholinergic. Some of these neurons have been shown to contain melanin-concentrating hormone (MCH), a neuropeptide implicated in regulating feeding, but the identities of the remaining neurons are unknown. We now report that nearly all AChE-immunoreactive neurons in the LHA express immunoreactivity for either MCH or for orexin, a peptide implicated in regulating wakefulness. Furthermore, most orexin neurons and MCH neurons appear to contain AChE. AChE immunoreactivity appears to be a key feature of nearly all of the diffusely-projecting cortical systems.