Usnic acid and atranorin are known as both sunscreen substances in natural lichen population and cytotoxic substances on human cell lines. Both substances were isolated from the acetone extracts of Cladonia foliacea and Pseudevernia furfuracea, respectively. Their photoprotective activities on irradiated human keratinocyte (HaCaT) cells and destructive effects on non-irradiated HaCaT cells were compared by a modified method in order to assess the effects on mitochondrial metabolic activity (MTT assay), membrane integrity (LDH assay), apoptosis (DAPI staining) and cytoskeleton integrity (TRITC-phalloidin staining). This study showed that usnic acid and atranorin have substantial photosensitizing activity, which appears to be linked to their crystallized forms in lichen populations and their decreased amounts in the spring and summer seasons, when ultraviolet B radiation is maximum. However, their cytotoxic, apoptotic and cytoskeleton deleterious activities may be a considerable obstacle for their use in human skin care.