Inflammation is a key event in the skin normally occurring in response to the constant exposure to environmental and endogenous stimuli as well as to accidental damage. It also plays a central role in the pathogenesis of major cutaneous pathologies, ultimately resulting in skin carcinogenesis. As the acute mild inflammatory process is mainly adaptive in nature, chronic inflammation is a multifactorial and complex noxious process, extremely difficult to combat. The wealth of data documenting the involvement of redoxdependent regulatory and damaging processes in the skin inflammation has prompted research on a steadily growing number of plantderived active substances, mainly polyphenols, and selected principally on the basis of their free radical scavenging and antioxidant properties. In spite of the wide recognition of their anti-inflammatory efficacy in vitro, the clinical use for the prevention and treatment of major skin inflammatory conditions is in most cases yet to be conclusively proven. The complex nature of the cutaneous inflammatory process involves oxygen (ROS), nitrogen (RNS) and lipid reactive species, but is also driven by other mechanisms highlighted in these recent years, related to the regulation of gene expression, and to metabolic and signaling pathways that are ROS/RNS-independent. The screening of the enormous array of plant secondary metabolites, first of all polyphenols, for new effective and safe anti-inflammatory agents should be rather directed towards molecules targeting specific inflammatory pathways recognized to be active in the peculiar skin compartment.