Substantial evidence that has been acquired over recent years indicates that keratinocytes play an active role in the generation and expression of protective immune responses in the skin. The constitutive production of immune and inflammatory mediators by unperturbed keratinocytes is low or absent. However, upon stimulation by environmental, physical, or chemical stimuli, a significant increase in the production of pro-inflammatory mediators can be observed both in vitro and in vivo. Keratinocytes play a role in the pathogenesis of chronic inflammatory disorders such as atopic dermatitis and psoriasis, in which amplification of inflammatory reactions critically depends on the crosstalk between infiltrating leukocytes and keratinocytes. Indeed, T cell-derived cytokines have been identified as the most effective triggers of expression of soluble and membrane-bound molecules by keratinocytes. In turn, these molecules are responsible for the recruitment and activation of T cells and other leukocytes, leading to amplification of the inflammatory reaction.Adv Psor Inflamm Skin Dis 2009;1(2):47–58.