The chemical tools that could be used to examine the function of histamine in the brain are considered together with the evidence linking histamine specifically with the hypothalamus. The distribution of histamine and the enzymes responsible for its synthesis and metabolism is consistent with there being both mast cells and histaminergic nerve terminals within the hypothalamus. Iontophoresis, mepyramine binding and histamine-stimulated adenylate cyclase studies suggest that both histamine H1- and H2- receptors are present in the hypothalamus. In addition, intracerebroventricularly injected histamine receptor agonists and antagonists affect many functions associated with the hypothalamus such as cardiovascular control, food intake, body temperature control, and pituitary hormones whose release is mediated via the hypothalamus, such as corticotropin, growth hormone, thyroid stimulating hormone, prolactin, gonadotropins and vasopressin. However, only in the case of thyroliberin release, prolactin release, body fluid control and blood pressure control is there evidence yet that such effects are mediated via histamine receptors actually in the hypothalamus. The effects of enzyme inhibitors suggest endogenous histamine may be involved in the physiological control of thyroid stimulating hormone, growth hormone and blood pressure, and the effects of receptor antagonists support a role for endogenous histamine in prolactin control. Otherwise, there is little evidence for a physiological role for endogenous, as against exogenous, histamine whether it be from histaminergic terminals or mast cells. In addition, few studies have tried to distinguish possible effects on presynaptic receptors, postsynaptic receptors, hypothalamic blood vessels or the hypophyseal portal blood vessels. It is concluded that although there is good evidence now linking histamine and the hypothalamus more specific studies are required, for instance using microinjection or in vitro techniques and the more specific chemical tools now available, to enable a clearer understanding of the physiological role of histamine in the hypothalamus.