Antihistamines are used frequently in adult and pediatric patients as first-line treatment for both allergic rhinitis and urticaria. There are several different antihistamines on the market, generally divided into first- and second-generation products. Although many of these show efficacy, there are significant differences in the side effect profiles of these medications, with resultant differences in their effect on quality of life and other outcomes. Although the most significant differences are between generations, there are considerations even within generations, especially regarding sedation and possible effects on learning. Other than specific situations in which sedation may be a desired effect, the second-generation antihistamines generally are preferred and the risks and benefits of individual drugs within this group need to be considered for each patient's specific circumstances.