Antihistamines inhibit the effects of histamine at H1 receptors. They have a number of clinical indications including allergic conditions (e.g., rhinitis, dermatoses, atopic dermatitis, contact dermatitis, allergic conjunctivitis, hypersensitivity reactions to drugs, mild transfusion reactions, and urticaria), chronic idiopathic urticaria (CIU), motion sickness, vertigo, and insomnia. First-generation antihistamines are highly lipophilic and therefore readily cross the blood-brain barrier, contributing to adverse central nervous system effects, including sedation, drowsiness, and decreased cognitive processing. Newer antihistamines were developed to decrease the adverse effects of first generation drug. "Second generation" antihistamines have higher specificity for binding to H1 receptors, lower affinity for non-histamine receptors, and are lipo-phobic (thus have poor penetration of the blood brain barrier). Third generation antihistamines are natural metabolites of second generation drugs, developed with the goal of improving clinical efficacy and minimizing side-effects. The purpose of this review was to compare the efficacy, effectiveness, and adverse effects of newer antihistamines in both adult and pediatric populations. The following key questions guided this review: 1. For outpatients with seasonal or perennial allergic rhinitis or urticaria, do newer antihistamines differ in effectiveness? 2. For outpatients with seasonal or perennial allergic rhinitis or urticaria, do newer antihistamines differ in safety or adverse effects? 3. Are there subgroups of patients based on demographics (age, racial groups, gender), other medications (drug-drug interactions), comorbidities (drug-disease interactions), or pregnancy for which one newer antihistamine is more effective or associated with fewer adverse effects?