Arsenicals are painful, inflammatory and blistering causing agents developed as chemical weapons in World War I/II. However, their large stockpiles still exist posing threat to public health. Phenylarsine oxide (PAO), a strong oxidant and a prototype arsenical is tested for its suitability to defining molecular mechanisms underlying arsenicals-mediated tissue injury. Topically applied PAO induces cutaneous erythema, edema and micro-blisters. These gross inflammatory responses were accompanied by the enhanced production of pro-inflammatory cytokines, ROS and unfolded protein response (UPR) signaling activation. To demonstrate the involvement of UPR in the pathobiology of these lesions, we employed chemical chaperone, 4-phenylbutyric acid (4-PBA) which attenuates UPR. 4-PBA significantly reduced PAO-induced inflammation and blistering. Similar to its effects in murine epidermis, a dose- and time-dependent upregulation of ROS, cytokines, UPR proteins (GRP78, p-PERK, p-eIF2α, ATF4 and CHOP) and apoptosis were observed in PAO-treated human skin keratinocytes NHEK and HaCaT. In addition, 4-PBA significantly restored these molecular alterations in these cells. Employing RNA interference (RNAi)-based approaches, CHOP was found to be a key regulator of these responses. These effects are similar to those manifested by lewisite suggesting that PAO could be used as a prototype of arsenicals to define the molecular pathogenesis of chemical injury.