Histaminergic neurons reside in the tuberomammillary nucleus of the posterior hypothalamus where histamine is synthesized by the specific enzyme,histidine decarboxylase (HDC),and send widespread projections to various brain areas.Four subtypes of histamine receptor (R) have been cloned.Among them,H1R,H2R,and H3R are expressed in the brain with distinctive distribution patterns.Here we reported the increasing understanding of histamine role in controlling wakefulness and of the interaction of histamine within the network regulating sleep-wake cycles,with particular emphasis on the recent progress made following studies on gene-manipulated mice.When H1R and HDC were genetically knockout (KO),these mice still exhibited a clear-cut and essentially the same circadian profiles and daily amounts of sleep and wakefulness as wild-type (WT) mice.