The main causal agent of skin aging, immune depression, and cancer is UV light. Photoprotective agents can be divided into 2 classes: those that prevent photon-induced damage (sunscreens) and those that counter the deleterious effects of UV exposure systemically. In this review, the cellular and molecular mechanisms underlying the photoprotective effects of a Polypodium leucotomos (PL) fern extract are outlined. The effects of PL have been characterized in vivo and in vitro. It inhibits generation of reactive oxygen species and prevents UV-induced DNA damage, isomerization, decomposition of trans-urocanic acid, and also UV-induced cell death. Furthermore, oral treatment with PL combined with narrowband UVB therapy significantly promotes repigmentation of patients with vitiligo. Together, these effects postulate PL as a natural photoprotectant and potential adjuvant to phototherapy of various skin diseases.