Cumulative clinical and laboratory evidence on histamine and its actions suggests that it has a pathophysiologic role in asthma. These findings have renewed interest in the potential therapeutic role of H1 antihistamines in this disease. A murine model of allergen-induced airway inflammation and methacholine-induced airway hyperresponsiveness has been used to clarify mechanisms of airway function, to identify potential therapeutic targets, and to investigate the effects of the H1-receptor antagonist fexofenadine. Findings suggest that there may be a role for second-generation antihistamines in treating asthma, with patient selection as well as dosing both important therapeutic considerations. Because high-dose therapy may be required to achieve a clinical response, agents with the widest therapeutic window and the lowest potential for sedation would offer the greatest therapeutic potential.