Histamine H₁-receptor blockers are used to treat all types of itch resulting from serious skin diseases such as atopic dermatitis, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life. The development of effective treatments requires a full understanding of the fundamental mechanisms of itch. Recent studies have indicated that the pathogenic mechanisms of itch also involve agonists other than histamine, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-mediating C-fibers via specific receptors on the nerve terminals. Histological observations have shown increased epidermal nerve densities in patients with atopic dermatitis, suggesting that the higher density is at least partly responsible for itch sensitization. This hyperinnervation is likely induced by an imbalance between nerve elongation and repulsion factors produced by keratinocytes. Neuronal matrix metalloproteinases are also involved in the penetration of nerve fibers into the extracellular matrix. Moreover, itch-mediating fibers such as gastrin-releasing peptide⁺ (GRP⁺) and Mas-related G-protein coupled receptor A3⁺ (MrgprA3⁺) fibers are present in the skin. Clinically, emollients or UV-based therapies can partly control epidermal nerve density, but new substances and classes of antipruritic drugs are needed. This review highlights recent knowledge regarding epidermal nerve fibers that are partly involved in itch sensitization, and discuss peripheral mechanisms and treatments of itch, especially in atopic dermatitis.