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The mast cell–nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell–nerve unit in itch biology.