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Histamine is not only a crucial cytokine in the periphery but also an important neurotransmitter and neuromodulator in the brain. It is known to act on metabotropic H1-H4 receptors, but the existence of directly histamine-gated chloride channels in mammals has been suspected for many years. However, the molecular basis of such mammalian channels remained elusive, whereas in invertebrates, genes for histamine-gated channels have been already identified. In this report, we demonstrated that histamine can directly open vertebrate ion channels and identified β subunits of GABAA receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric β channels, histamine evoked currents with an EC50 of 212 μm (β2) and 174 μm (β3), whereas GABA is only a very weak partial agonist. We tested several known agonists and antagonists for the histamine-binding site of H1-H4 receptors and described for β channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of α1β2 or α1β2γ2 subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a γ2 subunit-controlled manner. Despite the vast number of synthetic modulators of GABAA receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABAA receptors and may thus represent an endogenous ligand for an allosteric site.