¡@¡@Itch is an unpleasant sensation that provokes the desire to itch. It is the cardinal symptom of atopic dermatitis (AD), leading to poor quality of life with impaired school and work performance, causing burdens to families and societies. Current treatments against itch do not offer satisfactory result. Therefore, understanding its pathophysiology is important to develop appropriate therapy against itch. Itch results from activation of cutaneous nerve endings by peripheral mediators, including neuropeptides and cytokines, and by central nerve circuit processing to brain cortex. Specifically, itch in AD results from impaired skin barrier and aberrant skin immune responses. Transepidermal water loss (TEWL), an indicator for barrier function, and blood level of neuropeptide ƒÒ-endorphin, but not VIP nor substance P, are both independently associated with itch intensity. Further, the increased blood levels of ƒÒ-endorphin and IL-31, a Th2 cytokine related to itch, are significantly correlated in AD. The activation of the receptor of IL-31, IL-31R, in keratinocytes induces calcium influx and STAT3-dependent production of ƒÒ-endorphin. The genetic polymorphisms of ORAI1, an important protein in calcium influx and immune cell activation, are distinct among patients of AD from Japan and Taiwan. Further, IL-9, a cytokine produced by Th9 cells, induces IL-8 production through STIM1, a cellular partner of ORAI1, in skin keratinocytes. For central processing of itch, using near infra-red spectroscopy (NIRS) to measure the cortical activation, we demonstrated the distinct temporal sequences and spatial propagation of a pain- and itch-induced signals in human cortex.  The scientific integration and multi-disciplinary approach of immunology, dermatology, and neurology may increase our understanding of itch and help develop targeting therapy for the troublesome itch.