High-risk human papillomaviruses (HPVs) are known to be associated with different anogenital cancers including cervical, anal, penile, and vaginal cancers. They are also found to be responsible for the dramatic increases in oropharyngeal squamous cell carcinoma (OPSCC) observed in the United States and Europe. The model for how high-risk HPVs induce cancer formation comes from studies of cervical cancer which usually involves integration of the HPV into the human genome and subsequent changes due to induced chromosomal instability. Recent work, discussed here, however suggests that this model may not be completely correct. In addition, we summarize studies now done in OPSCC which demonstrate that the role of HPV in these cancers may be different from that in cervical cancer. Finally, we propose new models for how HPV may be involved in the formation of these 2 cancers.