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Summary: Itch is an unpleasant skin sensation that can be triggered by exposure to many chemicals, including those released by mast cells. The natriuretic polypeptide b (Nppb)-expressing class of sensory neurons, when activated, elicits scratching responses in mice, but it is unclear which itch-inducing agents stimulate these cells and the receptors involved. Here, we identify receptors expressed by Nppb neurons and demonstrate the functional importance of these receptors as sensors of endogenous pruritogens released by mast cells. Our search for receptors in Nppb neurons reveals that they express leukotriene, serotonin, and sphingosine-1-phosphate receptors. Targeted cell ablation, calcium imaging of primary sensory neurons, and conditional receptor knockout studies demonstrate that these receptors induce itch by the direct stimulation of Nppb neurons and neurotransmission through the canonical gastrin-releasing peptide (GRP)-dependent spinal cord itch pathway. Together, our results define a molecular and cellular pathway for mast cell-induced itch. : Solinski et al. describe a cellular and molecular pathway that couples mast cell activation to itch behavior. They show that mast cell mediators, serotonin, leukotriene-C4, and sphingosine-1 phosphate directly stimulate Nppb sensory neurons via Htr1f, Cysltr2, and S1pr1 receptors, and this results in itch responses that are elicited through a canonical spinal cord-GRP pathway. Keywords: itch, Cysltr2, S1pr1, Htr1f, Nppb, mast cell, Trpv1