Abstract UV is the most abundant human carcinogen, and protection from extensive exposure to it is a widespread human health issue. The use of chemicals (sunscreens) for protection is intuitive and efficacious. However, these chemicals may become activated to reactive intermediates when absorbing energy from UV, thus producing damage themselves, which may manifest itself in phototoxic, photoallergenic or photocarcinogenic reactions in humans. The development of safe sunscreens for humans is of high interest. Similar issues have been observed for some therapeutically used principles such as PUVA therapy for psoriasis or porphyrins for phototherapy of human cancers. Photoactivation has also been reported as a side effect of various pharmaceuticals such as the antibacterial fluoroquinolones. In this context, the authors have been involved over more than 20 years in the development and refinement of assays to test for photomutagenicity as an unwanted side effect of UV-mediated activation of such chemicals for cosmetic or pharmaceutical use. The initial years of great hopes for simple mammalian cell-based assays for photomutagenicity to screen out substances of concern for human use were followed by many years of collaborative trials to achieve standardization. However, it is now realized that this topic, albeit of human safety relevance, is highly complex and subject to many artificial modifiers, especially in vitro in mammalian cell culture. Thus, it is not really suitable for being engineered into a general testing framework within cosmetic or pharmaceutical testing guidelines. Much knowledge has been generated over the years to arrive at the conclusion that yes, photomutagenicity does exist with the use of chemicals, but how to best test for it will require a sophisticated case-by-case approach. Moreover, in comparison to the properties and risks of exposure to UV itself, it remains a comparatively minor human safety risk to address. In considering risks and benefits, we should also acknowledge beneficial effects of UV on human health, including an essential role in the production of Vitamin D. Thus, the interrelationships between UV, chemicals and human health remain a fascinating topic of research.