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Pruritus (itching) is one of the most prominent and distressing features of atopic dermatitis (AD). Patient scratching adds to the epidermal damage, thereby increasing trans epidermal water loss and drying, possibly leading to secondary infection and inflammation.This in turn results in more itching and more scratching. Antihistamines have traditionally been part of the standard therapy regimen for AD, but a clear under-standing of their differences, their effects, and their precise indications is essential if any benefits are actually to be gained from their use.The role of antihistamines in AD is adjunctive. The primary therapy relies on reducing inflammation with topical corticosteroids and/or calcineurin inhibitors, aswell as reducing skin dryness with emollients, as presented in previous chapters of this book. It has often been erroneously assumed that antihistamines possess general antipruritic effects and therefore that almost any antihistamine should be helpful in alleviating the vicious itch-scratch cycle of AD. Although histamine does appear to play a major role in AD pruritus, clinical studies do not support prescribing antihistamines in a generalized indiscriminate pattern. Antihistamines have a variety of pharmacokinetic profiles and proper-ties, which are differentially suited to subpopulations of AD patients with varying clinical presentations.Used under the right indications, specific antihistamines can benefit certain AD patients.This chapter will begin with an overview of the biology of histamine receptors and the effects they mediate. Next it will present the antihistamines which are most often used for AD. Then this chapter will review the findings of clinical studies on the efficacy of antihistamines for AD patients. Finally it will present differential indications for the selection of appropriate antihistamines for AD patients