The histaminergic system in the mammalian brain consists of neurons in the caudal hypothalamic tuberomamillary nucleus and their projections to essentially all parts of the brain. However, the density of histaminergic fibers varies in brain regions. Histamine is involved e.g. in regulation of sleep and wakefulness and hypothalamic endocrine control. Many brain structures related to addictive behavior receive moderate or high density of histaminergic fibers. The role of histamine and its receptors in addiction-related behaviors has not been studied extensively. Studies from our laboratory using ethanol-preferring rats suggest a role for neuronal histamine and its H3 receptor in ethanol-related behaviors. Histamine content is very high in alcohol-preferring rats in contrast to normal or alcohol non-preferring rats. Behavioral studies showed that the acute ethanol intake of alcohol-preferring rats was bidirectionally regulated in a concentration-dependent manner on H3 receptor ligands. Male histidine decarboxylase knockout (HDC KO) mice were then used to study the role of histamine in alcohol-induced stimulation of locomotor activity, impairment of motor coordination and conditioned place preference. HDC KO mice showed a weaker stimulatory response to acute ethanol than wild type (WT) mice. The HDC KO mice showed stronger ethanol-induced place preference than WT mice. Ethanol induced stimulation of locomotor activity in normal mice with a peak effect seen at 5 min post administration. H3R antagonist ciproxifan inhibited this alcohol-evoked stimulation. In conditioned place preference paradigm ciproxifan alone did not result in the development of place preference, but it potentiated the alcohol reward. These data support a role for brain histamine in the mechanisms of alcohol effects. Histaminergic neurotransmission seems to be necessary for the stimulatory effect of alcohol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings on both rats and mice also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.