An extensive body of research exists on CNS effects of H1-antagonists. There is great interest in this area due to the well-known adverse CNS effects associated with first-generation H1-antagonists, and the many new second-generation agents claiming to have nonsedative properties. Because the CNS effects of H1-antagonists are complex and cannot be reflected in one measurement, a variety of assessments of CNS function are required. These range from the subjective (e.g., self-rating of drowsiness) to the objective (e.g. 24 h EEG sleep latency, P300), and from the simple (e.g., critical flicker fusion) to the complex (e.g., actual driving). When these tests are applied to the evaluation of the H1-antagonists currently available, it is clear that there is a real distinction between the older first-generation H1-antagonists and the newer second-generation ones. At the recommended dosages, all the second-generation H1-antagonists are clearly less sedating in more patients than their predecessors. These newer medications do not cross the blood-brain barrier readily; are highly specific for H1-receptors; have little to no anticholinergic, antiserotoninergic, or anti-alpha-adrenergic effects; and do not enhance the adverse CNS effects of alcohol or other CNS-active substances such as the benzodiazepines. Since most second-generation H1-antagonists are found to be relatively nonsedating, their benefit/risk ratios will be determined more by their other properties such as non-CNS adverse effects (e.g., potential to cause cardiac arrhythmias), potency, onset of action, duration of action, ease of administration, and cost. The future role and usefulness of the older sedating H1-antagonists, given the availability of the safer second-generation agents, are unclear at the present time. When H1-antagonist treatment is indicated, physicians should recommend an effective H1-antagonist with a favorable clinical pharmacology profile and a wide margin of safety in patients of all ages. The common, often subclinical, adverse CNS effects produced by the old H1-antagonists remain a major concern and, therefore, these compounds are no longer medications of choice in the treatment of allergic rhinitis, allergic conjunctivitis, or urticaria.