The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H(3) receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications.