Publisher Summary This chapter focuses on the attempts to target gene expression to the epidermis and to develop models that will be relevant to both the skin carcinogenesis in particular and the epithelial carcinogenesis in general. It highlights the power of gene targeting to study carcinogenesis in vivo. An epidermal targeting vector have been developed and transgenic mice is established that express Ha-ras, fos, transforming growth factor α (TGFa), and the E6/E7 transforming genes of human papillomavirus type 18 (HPV-18) exclusively in the epidermis. Although the individual genes have distinct phenotypic characteristics, the stability of the preneoplastic and premalignant phenotypes produced by each line over extended time periods is consistent. This stability indicates not only the necessity of secondary events for progression, but also demonstrates that this transgenic mouse model appears to be ideally qualified to assess the nature of these events. In vivo co-operation experiments are described that assess the consequences of acquisition of an additional genetic event. The chapter evaluates potential application of these human keratin K1 gene (HK1) transgenic mice as environmental carcinogen/promoter test systems.