Eukaryotic cellular machineries including the genome face continuous challenge from environmental deleterious agents, as well as from the by products of their own metabolism. Our skin is the most important barrier. It protects us from xenobiotic and genotoxic agents including ultraviolet (UV) solar radiation and potential carcinogens, which are notorious for causing skin cancer. There is a rise in non-melanoma skin cancer (NMSC), which is diagnosed in more than a million people every year in the United States alone, and is also prevalent in the other Western countries. In addition to sunscreens, chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our extensive animal studies on silibinin, a non-toxic bioactive component in milk thistle, suggest that it has a strong potential to prevent skin cancer incidence, promotion and progression in response to chemical carcinogens and tumour promoters as well as UV radiation. Our data suggest that silibinin has multiple targets in the cell, and can be protective against the harmful effects of cytotoxic agents such as reactive oxygen species and inflammation. Further, silibinin modulates mitogenic and survival signalling, p53, Cip1/p21 and other cell cycle regulatory molecules to prevent UVB-induced skin carcinogenesis. Our ongoing studies also suggest the positive effect of silibinin on the repair of UVB-induced DNA damage in mouse skin. Overall, the protective efficacy of silibinin against skin cancer is supported by sound mechanistic rationale in animal and cell culture studies, and suggests its potential use for humans.