Available evidence indicates that histamine (HA) plays a neuroregulatory role in the waking state. Support for this proposal is provided by electrophysiological, lesion and pharmacological studies, as well as by fluctuations of HA levels according to a circadian pattern. Thus, 1) HA-containing neurons unit activity changes dramatically as a function of behavioral state across the sleep-wakefulness continuum, from 2.3 spikes/sec during active waking to virtual silence during slow wave sleep and REM sleep; 2) HA levels reach a minimum during the dark phase followed by an increase during the light period in rats kept under controlled environmental conditions; in addition histidine decarboxylase and HA-N-methyl-transferase activities are higher during darkness; 3) lesions or cooling of the posterior hypothalamus in the area where HA-immunoreactive neurons are located gives rise to a state of somnolence or hypersomnia; 4) 2-thiazolylethylamine, the predominantly H1-receptor agonist and thioperamide, the H3-receptor antagonist increase wakefulness in laboratory animals, while the HA synthesis inhibitor a-fluoromethylhistidine, the H1-receptor antagonists mepyramine, diphenhydramine and chlorpheniramine, and the H3-receptor agonist (R)-a-Me-histamine produce opposite effects.