Abstract Mammals have evolved neurophysiologic reflexes such as scratching to expel invading pathogens and noxious environmental factors. It is also well established that these responses are associated with chronic inflammatory diseases such as atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that the type 2 cytokines interleukin (IL)-4 and IL-13 directly stimulate sensory neurons and that chronic itch is dependent on neuronal IL-4Rα, the shared receptor subunit for IL-4 and IL-13. Based on our understanding of IL-4Rα signaling in immune cells, we hypothesized that downstream Janus kinase (JAK) signaling in sensory neurons would be a critical mediator of itch. Indeed, we find that both systemic JAK inhibition and interruption of JAK signaling in the nervous system can dramatically reduce itch. Further, sensory neuron-specific genetic deletion of JAK1 results in robust abatement of chronic itch in mice. Finally, in proof-of-concept translational studies, patients with recalcitrant chronic itch improved rapidly and dramatically in response to JAK inhibition. Thus, signaling mechanisms previously ascribed to the immune system may represent novel targets within the sensory nervous system for the treatment of pathologic sensory responses. Collectively, these studies reveal an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.