Clinical and epidemiological data are consistent with the hypothesis that human papillomaviruses (HPVs) are a factor in genital, particularly cervical cancer. Although HPV16 and 18 are found primarily in cervical malignancy, the transfection of HPV16 or 18 DNA into cervical cells results in immortalization but not tumorigenicity. The addition of activated Ha-ras, an oncogene found in some cervical cancers expressing HPV16 or 18, to HPV16-immortalized human cervical cells results in malignancy as proven by the formation of cystic squamous cell carcinomas by HPV16-Ha-ras cells in nude mice. This two-stage model utilizing relevant human cells demonstrates that HPVs play a critical role in cervical malignancy and provides a system for elucidating critical cellular changes associated with progression to malignancy.