Publisher Summary This chapter focuses on the isolation and utilization of the epidermal keratinocytes for oncogene research. Keratinocytes have been widely used as target cells for testing the activity of oncogenes in the epithelial neoplasia. Many experimental studies have utilized cultured mouse skin keratinocytes, where in vitro results can be analyzed in the context of a substantial experience in carcinogen-induced mouse skin tumors. Studies of the mouse keratinocytes have also revealed the biological consequences of expressing v-los and derivatives, neu, mutant p53, and transforming growth factor α (TGF-α ). These studies have focused on the participation of oncogenes as mediators of premalignant progression and malignant conversion. The effects of oncogenic DNA viruses have also been tested in keratinocytes and particular emphasis has been directed toward the expression of the simian virus 40 (SV40) and specific subtypes of human or bovine papilloma viruses (HPV, BPV) or their transforming sequences. The chapter also provides details of the techniques employed in the studies testing the influence of oncogenes on keratinocytes and several general conclusions from the results are presented.