Allergic contact dermatitis (ACD) is a common skin disease characterized by contact hypersensitivity to allergens, inflammation, and pruritus. In the majority of patients, contact dermatitis is caused by sensitization and subsequent epicutaneous challenge with environmental, occupational, or nutritional allergens. Most commonly encountered contact allergens is urushiol, produced by poison ivy, metals, such as nickel and cobalt, fragrance constituents, detergents, and food chemicals. These reactive chemicals haptenate skin proteins and produce a predominantly Th2-type allergic response. Inflammation results in the breakdown of the skin barrier and eczema. One of the major characteristics of ACD is persistent pruritus, leading to scratching behavior that further damages the skin and facilitates access by allergens and pathogens. While the immune response in ACD has been extensively investigated, little is known about the mechanisms leading to pruritus. The sensation of itch is initiated by excitation of sensory nerve fibers innervating the inflamed skin site. These fibers are activated by inflammatory mediators released by immune cells or skin tissue cells. In chronic contact dermatitis, antihistamine treatment is often insufficient to inhibit pruritus and inflammation, leaving limited treatment options. The nature of the histamine-independent inflammatory and pruritic pathways in chronic dermatitis, as well as the signaling mechanisms leading to their activation, are largely unknown. However, many experiments to find an itch-relieving agents in animal ACD model have been tried. ACD is often accompanied by spontaneous itch and pain. In a recent study, human subjects, previously sensitized to the contact sensitizer squaric acid dibutylester (SADBE), reported spontaneous itch and nociceptive sensations within an area of ACD produced by a subsequent application of the chemical. Within this area, heat stimuli that in normal skin elicit only pain sensation, elicited the additional sensation of itch and intradermal injection of certain pruritic chemicals evoked an enhanced itch. In addition to pain and itch, sensory nerves promote acute and delayed inflammatory responses in the skin in ACD and other pathological skin conditions. Nerve transection, anesthesia, or selective ablation of peptidergic C-fibers strongly inhibited both acute chemically induced inflammation and delayed sensitivity responses in rodent and human skin. Chemical stimulation of sensory nerve fibers triggers the local release of neuropeptides, such as substance P or calcitonin gene-related peptide (CGRP) that mediate neurogenic inflammatory responses, resulting in dilation of cutaneous vessels, plasma extravasation, and edema.