In rats, the cell bodies of the histaminergic neuronal system are clustered in five distinct cell groups (E1–E5) within the posterior hypothalamus. On the basis of tract tracing studies, these histaminergic subgroups have been regarded as one functional unit. In addition to its well-characterized role in arousal, locomotor activity, metabolism, feeding, drinking and behaviour, as well as in coordination of autonomic functions, histamine has been implicated in regulation of the hypothalamo–pituitary–adrenocortical axis during stress. To address the capacity of different histaminergic subgroups to respond to various challenges, we revealed c-Fos, the immediate early gene marker of activated neurons, in histamine synthesizing neurons by combining c-Fos immunocytochemistry with in situ hybridization of histidine decarboxylase (HDC) mRNA. Compared to the negligible colocalization of these markers in control rats, restraint, insulin-induced hypoglycaemia and foot shock resulted in specific activation of histamine synthesizing neurons of the E4 and E5 subgroup in the tuberomammillary region. Up to 36% of HDC mRNA-expressing cells show c-Fos immunoreactivity in the E5 region. In addition, some neurons of the E1, E2 and E3 histaminergic groups were activated after restraint stress. Many less c-Fos-positive histaminergic neurons were detected after immobilization and dehydration. Ether stress, acute hyperosmotic stimulus or injection of bacterial lipopolysaccharide did not activate hypothalamic HDC-positive neurons. These results suggest, for the first time, the functional heterogeneity of histaminergic neuron population, the components of which are recruited in a stressor- and subgroup-specific manner.