First-generation H1-antagonist antihistamines such as hydroxyzine have a significant ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but does not cause sedation. This lack of CNS effects may be due to cetirizine's greater selectivity or potency at H1 receptors in the brain, compared with its effects at the receptors involved in sedation, or it may result from the agent's relative exclusion from the CNS compartment. We compared cetirizine's activity at central H1 sites with the activity of hydroxyzine and terfenadine. We also compared the abilities of cetirizine and three other antihistamines to cross the blood-brain barrier. We found the drugs' potency at H1 receptors in the CNS to be similar to their activities in other tissues. However, their selectivity varied widely. Cetirizine, in fact, failed to bind at any of the receptors investigated except H1 sites, even at concentrations as high as 10 micron. Both hydroxyzine and D-chlorpheniramine crossed the blood-brain barrier in significant amounts. Terfenadine did so to a much lesser extent, and cetirizine passed into the CNS only half as readily as terfenadine. We suggest that cetirizine's reduced incidence of sedative side effects may stem partly from its selectivity for H1 receptors over sites involved in sedation, and partly from its relative exclusion from the CNS.