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Itch represents one of the most bothersome symptoms in allergic disorders and numerous dermatological and systemic diseases. Chronic itch has a dramatic impact on the quality of life. The pathophysiology of itch is diverse and involves a complex network of cutaneous and neuronal cells. Thus, we highlight the current pathophysiological aspects of itch together with new treatment options.Apart from histamine, several mediators and receptors including the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor, neurokinins/neuropeptides such as substance P, gastrin-releasing peptide, cytokines such as interleukin-31, autotaxin and the histamine H4 receptor have been identified for playing a role in the pathophysiology of itch. In the skin, tissue resident cells such as keratinocytes, mast cells and cells of the inflammatory infiltrate including lymphocytes and eosinophils have been described to interact with neuronal cells, for example via the release of neurotrophins, neuropeptides and cytokines, adding novel regulatory pathways for the modulation of itch. Accordingly, promising treatment strategies such as the neurokinin-1 receptor antagonist aprepitant have been introduced for a successful management of itch.In this review, we highlight novel key players in the pathophysiology of itch with subsequent introduction of promising, novel and experimental treatment strategies.