Australia has one of the highest rates of skin cancer globally, with two in three people being diagnosed by the age of 70. Whilst non-melanoma skin cancers are more common, melanoma is responsible for the majority of skin cancer-related deaths. The main contributors to 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 failure of recognition and elimination of developing skin tumours by immune surveillance. Another consequence of UV is the synthesis of vitamin D and its active metabolite, 1,25-dihydroxyvitamin D3 (1,25D) in skin cells. Epidemiological studies have linked vitamin D status to melanoma risk and outcome. Our studies have shown that the active vitamin D metabolite 1,25D and related compounds including 1,25-dihydroxylumisterol and tetrahydrocurcumin can inhibit UV-induced DNA damage, immune suppression and skin carcinogenesis. Phosphatase and tensin homolog (PTEN) and N-myc downstream regulated gene-1 (NDRG1) are proteins that are lost or suppressed during carcinogenesis and metastasis. We showed that levels of both these proteins are significantly reduced 24 h after UV in primary human skin cells and in Skh:hr1 mouse skin, but significantly increased with 1,25D treatment. We have also shown that 1,25D can increase levels of proteins that play a key role in nucleotide excision repair of UV-induced DNA damage. Our studies suggest a role for vitamin D compounds in the prevention of skin carcinogenesis and inhibition of melanoma cell growth. Vitamin D-like compounds that are less calcemic but photoprotective are promising for use in after-sun lotions to protect against acute UV damage while also preventing skin carcinogenesis.