The histaminergic and orexin/hypocretin (orx) neurons are located in the posterior hypothalamus. The orx neurons excite the histaminergic neurons, and both systems are essential in maintaining wakefulness. In narcoleptic patients not only the orx system is affected but also the histamine levels in the cerebrospinal fluid are reduced. Detailed information about the regulation of orx neurons by histamine has been missing. The zebrafish have very similar neurotransmitter systems as mammals. The transparency of the developing fish allows detailed studies on phenotypes of genetically modified fish, and the small size of the brains renders it possible to count neurons. Both male and female zebrafish had 41–45 (m 45±5, f 41±6) histaminergic neurons in the posterior hypothalamus. In larval zebrafish, translation inhibition of histidine decarboxylase (hdc) reduced histamine levels significantly and also reduced the number of orx neurons. This effect was rescued by coinjection of hdc mRNA. Overexpression of hdc in fish larvae increased the number of orx neurons, suggesting a bidirectional regulation of orx neuron number by histamine. Inactivation of one of the two tyrosine hydroxylases (th2) in larval zebrafish by morpholino oligonucleotides increased the number of histaminergic neurons and also the number of orx neurons. This finding may be relevant for understanding the complex regulation of modulatory neurotransmitter networks, which seems to be dynamic. Since the histamine levels are increased in the affected brain regions in Parkinson's disease, our findings suggest that dopamine may directly regulate the histaminergic neuronal network. Taken together, in zebrafish dopamine regulates the histaminergic network, which in turn exerts bidirectional regulation of the orx system.