Histamine can produce inotropic and chronotropic responses in both guinea pig and rabbit heart. In the guinea pig the responses are mediated primarily through stimulation of H2 receptors with H1 receptors being found mainly in left atria. In the rabbit H1 receptors predominate; H2 receptors are found only in right atria and are partially responsible for the chronotropic effect. H2 receptors are always associated with cyclic AMP, whereas H1 receptors are not. H2-histamine receptors and beta-adrenergic receptors have a number of properties in common. Stimulation of either receptor results in positive inotropic and chronotropic effects and increases in cyclic AMP and phosphorylase a. H2 and beta-adrenergic agonists will also both restore the action potential in K+-depolarized cardiac muscle. H1 and alpha-agonists, on the other hand, will also produce an inotropic effect. The effect is not dependent on cyclic AMP and can only be demonstrated under certain conditions. Neither agonist will restore the action potential in depolarized cardiac tissue. It is concluded that, although H2 and beta-agonists and H1 and alpha-agonists may have a common mechanism of action, the two groups of drugs (H2, beta versus H1, alpha) differ from each other with regard to mechanism.