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Itching (pruritus) is perhaps the most common symptom associated with numerous skin diseases and can be a lead symptom of extracutaneous disease (e.g., malignancy, infection, metabolic dis‑ orders). Also in atopic dermatitis itching sensations constitute one of the most prominent and distressing features. However, the most characteristic response to itching is the scratch reflex: a more or less voluntary, often sub‑conscious motor activity, to counteract the itch by slightly painful stimuli. The benefit of a short‑termed relieve from itching through this scratch reflex though is counteracted by a simultaneous damage of the epidermal layer of the skin which leads to increased transepidermal water loss and drying, which in turn results in a cycle of more itching and more scratching. A be‑ wilderingly wide range of peripheral itch‑inducing stimuli generated within or administered to the skin are able to trigger pruritus, one of them being histamine. Based on early experiments, histamine has been suggested to may play a key role in the pathogenesis of AD. This is reflected by a history for antihistamines in the therapeutic medication of AD patients. Antihistamines are believed to share a common antipruritic effect and therefore are prescribed to almost any AD patient suffering from itch to act alleviating. This general assumption has been proved to be wrong. To assess the benefit of antihistamines in the treatment of AD in a better way, their mechanisms and specific effects need to be understood more precisely. In particular their precise indication is crucial for successful use. This book chapter will therefore summarize and assess the role of histamine in AD and the efficacy of antihistamines in its treatment based on results of basic research and clinical studies.