Many antihistamines exhibit inhibition of mediator release from mast cells and basophils, in in vitro studies in addition to H1 antagonism. The underlying mechanism is unclear but is unrelated to H1-receptor antagonism. Clinical studies of antihistamins in antigen challenge and seasonal allergy demonstrate reduction of mast cell mediators in nasal lavage. It is not known what mechanism(s) underly these observations, although the concentrations required in in vitro studies suggests that a direct effect on mast cells is unlikely. Furthermore, the therapeutic contribution of this effect is difficult to assess because of concomitant clinically significant H1 antagonism. This and other potential anti-allergic effects may enhance the therapeutic benefit of antihistamines and long-term studies are underway to explore this possibility.