In response to abiotic and biotic stressors, numerous polyphenols (PPs) are synthesized from phenylalanine by higher plants, amid many other plants that are poisonous for insects, birds, animals, and humans. PPs are also widely recognized by botanical dermatology as major plant constituents inducing allergic reactions, contact dermatitis, phytodermatoses, and photophytodermatoses. Notwithstanding these clinical observations, thousands of cosmetic/dermatological preparations based on PP-containing plant extracts or pure PPs emerge yearly with the claims of photoprotection, chemoprevention of skin tumors, anti-aging, wound healing, etc. However, because of their peculiar physical, chemical, and biological properties, PPs could be a double-edged sword for human skin, exerting both protective and damaging actions. Here, we distinguish direct and indirect anti- and pro-oxidant properties of PPs, their interactions with major xenobiotic metabolic systems and sensors/receptors of environmental hazards, anti- and proinflammatory potential, and photoprotection versus photosensitization.