© 2020, The Author(s). Purpose of Review: Skin cancers account for more than 40% of all cancers in the USA and continue to rise in incidence. It is prudent to understand the current burden and pathogenesis of photocarcinogenesis and preventive measures. Recent Findings: Insights into recently discovered mechanisms have paved way for potential targets for prevention and therapeutics. Nicotinamide has shown promising results as an oral chemopreventive agent. UVB affects the DHODH pathway of pyrimidine synthesis via STAT 3. DHODH inhibition by leflunomide may be a potential targeted chemoprevention strategy. A photolyase containing sunscreen, which repairs UV-damaged DNA, effectively reduced new precancerous lesions. Several antioxidants and anti-inflammatory agents including many phytochemicals ameliorate the process of photocarcinogenesis in preclinical and clinical studies, e.g., green tea polyphenols, Polypodium leucotomos extract, and Timosaponin A III. Diet can potentially affect skin cancer risk by its ability to modify oxidative stress and cell signaling pathways. Summary: Photocarcinogenesis is a multi-step process. An in-depth understanding is instrumental in development of novel agents for prevention and treatment of skin cancers.