The pathophysiologic effects of histamine in anaphylaxis have been shown to be mediated through H1 and H2 receptors, individually and in combination. H1 receptors mediate coronary artery vasoconstriction, wheezing, cutaneous vascular permeability, and possibly an increase in pulse rate. H2 receptors stimulate ventricular and atrial inotropy, arterial chronotropy, coronary vasodilation, and rises in basophil cyclic adenosine 3':5' monophosphate (cyclic AMP). (Neither receptor mediates increases in cyclic AMP in mast cells.) H1 and H2 receptors in combination seem to be most potent in mediating flush, headache, increases in pulse pressure, and decreases in diastolic blood pressure. Clinical trials have been conducted to determine the efficacy of H1 and H2 antagonists in preventing anaphylactic reactions to plasma expanders, anesthesia-inducing agents, morphine, and radiocontrast material. Concurrently, retrospective observations of the prevention of anaphylactic reactions to chymopapain have been recorded. Despite some conflicting and inconclusive data, the sum of these studies indicates that pretreatment with a combination of H1 and H2 antagonists is more effective than H1 antagonists alone in preventing reactions to these agents. These results, when added to the available knowledge of the physiology of histamine release, support the preferential use of H1/H2 antagonist combinations in the prevention and treatment of anaphylaxis and anaphylactoid reactions.