The p53 tumor suppressor gene and gene product are among the most diverse and complex been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific 'signature' mutations that can result in oncogenic transformation. There are certain 'hot-spots' in the p53 gene where mutations are commonly found that result in a mutated dipyrimidine site. This review discusses the role of p53 from normal function and its dysfunction in precancerous lesions, nonmelanoma and melanoma skin cancers. Additionally, molecules that associate with p53 and alter its function to produce neoplastic conditions are also explored in this chapter.