A recent increase in the number of young patients (often nonsmokers) developing head and neck squamous cell carcinoma (HNSCC) has been documented, however, there remains no clear evidence to support the significance of any single determinant. The typical HNSCC arises as a result of a multistep process and the progression model involving multiple genetic and epigenetic events is thought to be relatively consistent. While the progression model itself may be consistent, detection methods used in genomic studies are variable and all have their limitations. This article reviews changes at a molecular level in the typical HNSCC patient (the over 40 year old male smoker) and compares the profile to that of the young adult with HNSCC. Human papillomavirus infection with high risk types 16 and 18 has widely been reported as one of the prominent mechanisms behind the development of oropharyngeal cancer. A review of recent studies in relation to HPV and HNSCC is undertaken in this article, in an effort to examine the role that HPV plays in the development of HNSCC in young adults.