Ultraviolet (UV) irradiation causes multifaceted damage to the skin and adjacent tissue layers, and is one of the leading causes of premature skin aging, immunosuppression and carcinogenesis. Photoprotection can be achieved by the use of sunscreens and also by systemically administered compounds that fight the deleterious biological effects of UV exposure, or preferably both. In this review, we summarize the current knowledge on the tissue, cellular and molecular mechanisms underlying the photoprotective effect of Polypodium leucotomos fern extract. P. leucotomos blocked the deleterious effect of UV irradiation both in vivo and in vitro. The molecular basis of photoprotection relies on its ability to inhibit free radical generation, prevent photodecomposition of both endogenous photoprotective molecules and DNA, and prevent UV-induced cell death. Its complete loss of toxicity combined with its multifactor protection makes it a valuable tool not only for direct photoprotection, but also as an efficacious adjuvant to phototherapy of various skin diseases.