The sedation related to first-generation antihistamine use has been shown to compromise performance at school and at work, impair driving, and decrease the ability to handle tasks that require a high degree of alertness or concentration. Second-generation antihistamines are less likely to produce sedation. Loratadine, cetirizine, and fexofenadine are the most commonly prescribed second-generation antihistamines. Many tests have been conducted to assess the central effects of these three drugs. Compared with placebo, at recommended doses loratadine is not associated with performance impairment. Cetirizine, at recommended doses, has been shown to impair performance and cognition in several studies, although to a much lesser degree than older antihistamines. Clinical trials show fexofenadine is nonsedating, even at very high doses; psychomotor and driving tests reinforce these findings. Loratadine, cetrizine, and fexofenadine all have excellent safety records. Their cardiovascular safety has been demonstrated in drug-interaction studies, elevated-dose studies, and clinical trials. These three antihistamines have also been shown safe in special populations, including pediatric and elderly patients.