Benign tumors that form following chemical initiation and promotion in the mouse skin can be grouped into two classes. The majority of papillomas do not progress to squamous cell carcinoma (SCC), and these are designated as low-risk or terminally benign papillomas. In contrast, a much smaller group forms the true precursor to the SCC, and these have a significantly higher frequency and rate of malignant conversion than the bulk of low-risk papillomas. In standard two-stage carcinogenesis studies both tumor types are present, but grossly indistinguishable. Here we describe properties and potential origins of high-risk papillomas and discuss the relevance of this model for certain human cancers with defined premalignant states.