Cardiac anaphylaxis refers to the functional and metabolic changes in the heart caused by the anaphylactic release of histamine and vasoactive products of arachidonic acid cascade by mast cells and basophils. As in most type I hypersensitivity-based diseases, histamine plays a key role in the pathophysiology of cardiac anaphylaxis. In the heart, mast cell activation and histamine release are controlled by multiple endogenous mechanisms, including adrenergic neural control, histamine-dependent negative feedback operated through H2 receptors, and the endogenous generation of nitric oxide (NO) and carbon monoxide (CO). All these mechanisms can be targeted by substances that have revealed a clear-cut effect in blunting cardiac anaphylaxis in experimental animal models, and could be developed as potential, novel anti-anaphylactic drugs. In this article, we discuss new findings and significant trends related to this topic.