Histamine receptor type 3 was discovered in 1983 by Schwartz and coworkers and cloned in 1999. The expression of histamine receptor type 3 is largely confined to the central nervous system, where differential transcriptional and posttranscriptional processing lead to a high degree of molecular and functional heterogeneity. Histamine receptor type 3 has unique properties including constitutive activity in vivo and the recruitment of plasticity-related signal transduction pathways, including Gαi/o-proteins, adenylyl cyclase, phospholipase A2, mitogen-activated protein kinase and Akt/glycogen synthase kinase 3 signalling. These make the histamine receptor type 3 the most prominent target for histaminergic drug development. Histamine receptor type 3 can function both as an autoreceptor and as a heteroreceptor. As an autoreceptor on histaminergic neurons, histamine receptor type 3 activation inhibits cell firing, histamine synthesis and release. As a presynaptic heteroreceptors on other neurons, histamine receptors type 3 abundantly control the outflow of various neurotransmitters, including biogenic amines, acetylcholine, glutamate and γ-amino butyric acid. The histamine receptor type 3 functioning is associated with cognition, behaviour, wakefulness and sleep regulation, locomotion, appetite regulation and pain perception.