Skin cancers are the most common cancer in Australia, and also the most costly to treat. The key initiating events in ultraviolet radiation (UV)-induced skin carcinogenesis are UV-induced DNA damage, some of which is inadequately repaired, resulting in mutations, and UV-induced immune suppression, which results in developing skin tumours not being recognised and eliminated by immune surveillance. Vitamin D and its active metabolite, 1,25-dihydroxyvitamin D3 (1,25D), are synthesised in skin cells following exposure to ultraviolet radiation. Our studies showed that 1,25D, when applied immediately after UV, can inhibit UV-induced DNA damage, immune suppression as well as skin carcinogenesis in a well accepted 40 week murine model of photocarcinogenesis. We further tested low calcemic vitamin D analogs and vitamin D-like compounds and demonstrated similar protective effects with 1,25-dihydroxylumisterol and tetrahydrocurcumin. Yet several of the potentially photoprotective agents we have examined in acute and chronic UV studies have reduced UV-generated DNA damage and UV-induced immune suppression, but have not reduced photocarcinogenesis in the long term murine model. Therefore, our studies show that reductions in UV-induced DNA damage and immune suppression alone are not necessarily predictive of potential for photoprotective agents to prevent skin carcinogenesis in the long term, and thus, there is a need to find more reliable markers. If there were early markers to indicate whether photoprotective agents were likely to reduce tumours in a long term photocarcinogenesis model, this would make for a more time- and cost-efficient process for identifying suitable agents for this lengthy testing.