Malignant cancer emerges from normal healthy cells in a multistep -process that involves both genetic and epigenetic lesions. Both genetic and environmental inputs participate in driving the epigenetic changes that occur during human carcinogenesis. The pathologic changes seen in DNA methylation and histone posttranslational modifications are complex, deeply intertwined, and act in concert to produce malignant transformation. To better understand the causes and consequences of the pathoepigenetic changes in cancer formation, a variety of experimentally tractable human cell line model systems that accurately reflect the molecular alterations seen in the clinical disease have been developed. Results from studies using these cell line model systems suggest that early critical epigenetic events occur in a stepwise fashion prior to cell immortalization. These epigenetic steps coincide with the cell's transition through well-defined cell proliferation barriers of stasis and telomere dysfunction. Following cell immortalization, stressors, such as environmental toxicants, can induce malignant transformation in a process in which the epigenetic changes occur in a smoother progressive fashion, in contrast to the stark stepwise epigenetic changes seen prior to cell immortalization. It is hoped that developing a clearer understanding of the identity, timing, and consequences of these epigenetic lesions will prove useful in future clinical applications that range from early disease detection to therapeutic intervention in malignant cancer.