Antihistamines are useful medications for the treatment of a variety of allergic disorders. Second-generation antihistamines avidly and selectively bind to peripheral histamine H1 receptors and, consequently, provide gratifying relief of histamine-mediated symptoms in a majority of atopic patients. This tight receptor specificity additionally leads to few effects on other neuronal or hormonal systems, with the result that adverse effects associated with these medications, with the exception of noticeable sedation in about 10% of cetirizine-treated patients, resemble those of placebo overall. Similarly, serious adverse drug reactions and interactions are uncommon with these medicines. Therapeutic interchange to one of the available second-generation antihistamines is a reasonable approach to limiting an institutional formulary, and adoption of such a policy has proven capable of creating substantial cost savings. Differences in overall efficacy and safety between available second-generation antihistamines, when administered in equivalent dosages, are not large. However, among the antihistamines presently available, fexofenadine may offer the best overall balance of effectiveness and safety, and this agent is an appropriate selection for initial or switch therapy for most patients with mild or moderate allergic symptoms. Cetirizine is the most potent antihistamine available and has been subjected to more clinical study than any other. This agent is appropriate for patients proven unresponsive to other antihistamines and for those with the most severe symptoms who might benefit from antihistamine treatment of the highest potency that can be dose-titrated up to maximal intensity.