With its unique structure and large numbers of immune cells, the skin is one of the body's first lines of defense against attacks from the environment. It is also innervated by a dense meshwork of primary sensory neurons, including nociceptive fibers specializing in the detection and transduction of harmful stimuli that can elicit pain. This tissue is, therefore, a key organ for studies of neuroimmune interactions and their impact on the host response to environmental challenges. Neuroimmune crosstalk in the skin is crucial for the regulation of inflammation, tissue repair, and host defense against pathogens. A better understanding of this regulation would facilitate the identification of new molecular targets for the treatment of skin diseases.