Human papillomaviruses (HPVs) are a major cause of cancer globally, including cervical cancer. The HPV ‘early’ proteins, E6 and E7, are the chief oncoproteins involved in cancer progression. These oncoproteins are more highly expressed in high-grade dysplasias and invasive cancer coincident with reduced viral DNA replication and reduced production of infective progeny virions. The E6 and E7 oncoproteins interact with several cellular proteins—classically TP53 and RB1, respectively—leading to the degradation of several of these proteins, although all interactions do not necessarily result in the degradation of a cellular protein. HPV infection is also associated with viral and host DNA methylation changes, many of which also occur in cancer types not associated with HPV infection. The E6 and E7 interactions with cellular proteins and DNA methylation changes are associated with changes in the integrity of key cellular pathways that regulate genomic integrity, cell adhesion, the immune response, apoptosis, and cell cycle control. The alterations in key cellular pathways may provide useful biomarkers to improve the sensitivity of current cancer screening methods, such as the Papanicolaou test. This review provides a detailed summary of the interactions of E6 and E7 with cellular proteins and alterations in cellular DNA methylation associated with HPV infection. The importance of molecular biomarkers to the clinical setting, underserved populations, and general public health is discussed. Cancer 2008;113(10 suppl):2981–94. Published 2008 by the American Cancer Society.