Data from rat models for alcohol preference and histidine decarboxylase knockout (HDC KO) mice suggest that brain histamine regulates alcohol-related behaviors. Histamine levels are higher in alcohol-preferring than in alcohol-nonpreferring rat brains, and expression of histamine H(3) receptor (H(3)R) is different in key areas for addictive behavior. H(3)R inverse agonists decrease alcohol responding in one alcohol-preferring rat line. Conditioned place preference induced by alcohol is stronger in HDC KO mice than in control mice. The HDC KO mice display a weaker stimulatory response to acute alcohol than the wild-type (WT) mice. In male inbred C57BL/6 mice the H(3)R antagonist ciproxifan inhibits ethanol-evoked stimulation of locomotor activity. Ciproxifan also potentiates the ethanol reward, but does not alone result in the development of place preference. At least in one rat model developed to study alcohol sensitivity high histamine levels are characteristic of the alcohol-insensitive rat line, and lowering brain histamine with a HDC inhibitor increases alcohol sensitivity in the tilting plane test. However, the motor skills of HDC KO mice do not seem to differ from those of the WT mice. Current evidence suggests that the histaminergic system is involved in the regulation of place preference behavior triggered by alcohol, possibly through an interaction with the mesolimbic dopamine system. Histamine may also interact with dopamine in the regulation of the cortico-striato-pallido-thalamo-cortical motor pathway and cerebellar mechanisms, which may be important in different motor behaviors beyond alcohol-induced motor disturbances. H(3)R ligands may have significant effects on alcohol addiction.