The effect of histamine on the release of endogenous noradrenaline and 5-hydroxytryptamine (5-HT) has been examined in slices of rat cerebral cortex. Histamine was found to produce a marked release of both amines from rat cerebral cortex at concentrations between 0.1 and 1 mM. This response to histamine was relatively resistant to removal of calcium ions from the incubation medium when compared to the release evoked by depolarising potassium stimuli. The response to 1 mM histamine was not, however, significantly inhibited by the H 1-antagonist mepyramine (1 μM) or the H 2-antagonist cimetidine (100 μM). Furthermore, impromidine which is both a potent H 2-agonist and a potent H 3-antagonist was without effect on the basal and histamine-stimulated release of endogenous noradrenaline and 5-HT. The response to histamine was, however, significantly attenuated by nisoxetine, fluoxetine and imipramine which are inhibitors of the amine uptake systems. The results of this study show that high concentrations (0.1 to 1 mM) of histamine can produce a marked increase in the release of endogenous 5-HT and noradrenaline from rat cerebral cortex, apparently via a non-receptor mechanism. This effect will need to be borne in mind in interpreting biochemical and behavioural responses to histamine in this concentration range.