So far it has not been possible to assign with certainty a part for histamine in normal physiology. Considering its omnipresence and wide range of actions, when liberated or injected, this situation is envisaged 'not without an inner feeling of disappointment' (Rocha e Silva, 1955).There are no methods available for the accurate estimation of small changes in the histamine concentration of blood or plasma such as might possibly occur during increased activity of certain tissues, e.g. the parietal cells of the gastric mucosa. It has been suggested that the estimation of histamine in the urine is more likely to give information about the release of histamine in the body than investigations on venous blood (Adam, 1950;Gaddum, 1951). This promising approach is limited by the fact that the food commonly eaten by man and laboratory animals contains substantial amounts of histamine, part of which is excreted in the urine. Further, with such a diet intestinal bacteria decarboxylate histidine to histamine, constituting an additional source of exogenous histamine (Schayer, Wu & Smiley, 1954). Large amounts of urinary histamine derived from exogenous sources are likely to conceal increases in urinary histamine derived from increased production or release of endogenous histamine. Schayer, Davis & Smiley (1955) showed that in rats exogenous urinary histamine could be diminished by giving the animals a protein-free diet containing antibacteral agents. This procedure, however, seems hardly suitable for experiments over a long period of time.The complications due to exogenous histamine can now be overcome. It has been observed that in rats raised and maintained on a synthetic histamine-free diet the distribution and urinary excretion of histamine is the same as in germ-free-reared rats, accordingly devoid of intestinal bacteria, and fed on the same diet (Gustafsson, Kahlson & Rosengren, 1957). This similarity indicates that, even in normally kept rats fed as mentioned, histamine from exogenous sources does not contribute detectably to the urinary excretion.