Rats and mice were rendered tolerant to histamine by prolonged treatment with the amine. Possible mechanisms of adaptation were examined in these species. Increased binding of histamine to nonmast cell sites in the skin and lung of the mouse and the lung and ileum of the rat was observed. The ability of the blood serum to bind histamine (histaminopexy) was increased in the histamine-treated mouse although serum from the rat possessed a lower binding capacity compared with controls. Prolonged administration of histamine to both species resulted in significant but relatively small increases in both in vivo and in vitro catabolism of histamine in several tissues. A reduction in the histamine-forming capacity of the kidney was observed in histamine-adapted rats. Adrenal changes were noted after histamine treatment and included increased weight in both species, lowered noradrenaline, and an increased level of adrenaline in the rat adrenals. It appears that no single mechanism examined explains the tolerance obtained but that the effect is a combination of factors.