In the allergic reaction, mast cells degranulate, releasing inflammatory mediators including histamine. The H1 receptor antihistamines have been developed over the past 50 years to minimize the clinical symptoms caused by this reaction. Currently, H1 antihistamines are taken by approximately 30 million Americans per year. First-generation H1 antihistamines, some of which are available without prescription, can cross the blood-brain barrier and have been reported to produce sedation in 10% to 25% of users. When activities that require mental alertness and concentration are considered--school performance and driving, for example--this effect is troublesome and even potentially hazardous. The newer, second-generation H1 antihistamines (eg, astemizole, cetirizine, loratadine, terfenadine) have difficulty entering the brain because they are typically large, lipophobic molecules that have charged side chains and are extensively bound to protein. Consequently, they appear to induce sedation less commonly than classic antihistamines. Since a primary tenet of medical care has always been primum non nocere--first of all, in the management of clinical illness, do no harm--it is important in these "State-of-the-Art Perspectives" to address the comparative safety of the H1 antihistamines. A number of methodologies have been used to make this assessment, including the multiple sleep latency test, the P300 (P3) wave of the auditory-evoked potential, self-ratings, visual function tests, and tests that measure reaction times, visual-motor coordination, and driving skills. The effect of the interaction of H1 antihistamines with alcohol and tranquilizers also has been examined.(ABSTRACT TRUNCATED AT 250 WORDS)