This study was conducted to identify and clarify the actions of pulmonary and systemic H1 and H2 receptors by utilizing specific histamine receptor antagonists. Histamine was infused in anesthetized dogs during control conditions, after H2 receptor blockade with metiamide, after H1 receptor blockade with chlorpheniramine, and after combined H1 and H2 receptor blockade. Histamine infusion, alone, induced marked systemic vasodilatation, pulmonary vasoconstriction, and transient increases in cardiac output and heart rate. H2 receptor blockade prevented the systemic vasodilatation and potentiated the pulmonary vasoconstriction induced by histamine. H1 receptor blockade augmented the systemic vasodilatation, prevented the pulmonary vasoconstriction, and increased the cardiac output and heart rate responses induced by histamine. Thus, H2 receptors appear to mediate the vasodilatation, tachycardia, and increased cardiac output induced by histamine, whereas H1 receptors appear to mediate the vasoconstrictor and the minimal cardiac depressant actions of histamine. Histamine stimulates only H1 and H2 receptors, since combined H1 and H2 receptor antagonism prevented almost all of the cardiovascular actions of histamine.