The tumor suppressor protein p53 plays a critical role in the orchestration of the cellular responses to a variety of genotoxic and cytotoxic stresses. Mutations or functional inactivation of p53 seriously compromise these cellular processes and foster tumor development. p53 is the most frequently mutated gene in human cancers and over 90% of human non-melanoma skin cancers (NMSC) harbour p53 mutation. It plays a vital role in the control of the immediate and adaptive responses to ultraviolet radiation (UV) and the onset of NMSC. During the process of photocarcinogenesis, UV-specific p53 mutations occur early in the keratinocytes resulting in the loss of the wild type p53 function and continued UV exposure leads to clonal expansion of p53-mutated keratinocytes and promotion of skin tumors. Precisely how clones of keratinocytes containing such mutations, in an apparently normal epidermis, progress to a malignant carcinoma is unknown. Further examination of the functional significance of these UV-p53 mutations in affecting the immediate and adaptive responses of the skin to UV is critical to the development of effective prevention and therapeutic strategies for human skin cancer. The purpose of this article is to provide an overview of accumulating evidence pointing towards a critical role for p53 mutation in photocarcinogenesis.