Allergic rhinitis (AR) is associated with histamine-mediated physiologic events. The currently used histamine antagonists are all inverse agonists that bind and inactivate histamine H1 receptors. Second-generation antihistamines are much more H1-receptor selective with less central nervous system penetration than first-generation agents. Antihistamines typically are more effective in seasonal than perennial AR and do not demonstrate significant relief of nasal congestion. The recent availability of some second-generation antihistamines as over-the-counter products clearly places them as the preferred first-line treatment for mild to moderate AR based on safety when compared with first-generation over-the-counter antihistamines. The remaining prescription-only second-generation antihistamines, fexofenadine, desloratadine, and levocetirizine, all have unique attributes. Antihistamines in oral, intranasal, or intraocular formulations will likely remain among the mainstays of allergy therapeutics.