Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide. Carcinoma of the uterine cervix is the most common female malignancy in the world. While cervical cancer is a worldwide disease, oral cancer has the highest incidence in developing countries, especially among tobacco and alcohol users and betel quid chewers. A strong association of cervical and oral cancer with high-risk human papillomavirus (HPV) 16 and 18 infections underlines the importance of the virus in the pathogenesis of these squamous cell carcinomas. Functionally high-risk HPV infection contributes to carcinogenesis and tumor progression predominantly through the actions of two viral oncogenes, E6 and E7. The E6 and E7 genes have been studied in different patient populations and a number of variants have been described. More than 40 variants have been classified and may be related to differences in progression of squamous intraepithelial lesions. The transcription factor, NFκB and its activation pathways are frequently targeted by viruses and aberrant constitutive activation of NFκB is frequently found in human tumors of diverse tissue origin. Diet–gene interactions are also likely to contribute considerably to the observed inter-individual variations in HPV associated cancer risk, in response to exposures to the nutritional factors that have the potential to promote or protect against cancer.