Skin irritation is a complex phenomenon that involves resident epidermal cells, fibroblasts of dermis, and endothelial cells as well as invading leukocytes interacting with each other under the control of a network of cytokines and lipid mediators. Keratinocytes play an important role in the initiation and perpetuation of skin inflammatory reactions through the release of, and responses to cytokines. While resting keratinocytes produce some cytokines constitutively, a variety of environmental stimuli, such as tumor promoters, ultraviolet light and chemical agents, can induce epidermal keratinocytes to release inflammatory cytokines (IL-1, TNF-alpha), chemotactic cytokines (IL-8, IP-10), growth promoting cytokines (IL-6, IL-7, IL-15, GM-CSF, TGF-alpha) and cytokines regulating humoral vs. cellular immunity (IL-10, IL-12, IL-18). The role of cytokines in xenobiotics-induced skin irritation and the early molecular events that follow the treatment with irritant compounds will be discussed.