Research in the Balmain laboratory has been focused on developing a deep understanding of how cancers emerge from normal tissues through a series of steps, from the first initiating event in single cells to early stage preneoplasia and then progression to metastasis. In particular, we have sought to investigate how environmental carcinogens, including those that cause mutations and others that act as non-mutagenic tumor promoters, cause the outgrowth of cell clones that ultimately develop into malignancies. In order to address these questions, we generated genetically heterogeneous mouse populations by crossing different strains and species of mice, and exposed them to different mutagens and tumor promoters, to investigate how genes and environmental factors conspire to induce cancer. Our data have led to the identification of the initiating mutation for skin cancers induced by carcinogens, and the stem cells in which these mutations occur. Using lineage tracing of stem cells during multistage carcinogenesis, we have demonstrated that initiation of benign tumor growth, and progression to malignancy are clonal events, i.e. they involve specific changes in single cells. The use of heterogeneous mouse populations that mimic the genetic diversity of humans has allowed us to explore how networks of genes, working together, induce these events. Gene expression network analysis has identified high plasticity cell states that evolve in early stage tumors in response to chronic inflammation induced by tumor promoters, eventually causing leading to progression. Some of these same cell states are induced by treatment of fully malignant tumors with chemotherapeutic agents, possibly providing new routes to development of resistance to therapy. These mouse models have shown that genomic mutations are critical for cancer development from single cells, but emphasize the importance of the process of tumor promotion and chronic tissue damage in causing outgrowth of otherwise latent mutated cells, leading to increased cancer incidence. Whole genome sequencing of tumors induced in mice by known or suspected human carcinogens has shown that perhaps 80% of carcinogens do not act through mutational mechanisms, but are more likely to promote tumor development from cells carrying pre-existing spontaneously arising mutations in normal tissues. Further studies are underway to address the mechanisms by which promoters cause these effects, to identify promoters in the environment, and identify new strategies for cancer prevention based on inhibition of the promotion stage.