Head and neck squamous cell carcinoma (HNSCC) can primarily be attributed to alcohol consumption, tobacco use and infection with human papilloma virus. The heterogeneous nature of HNSCC has exposed a lack of tools for clinicians to provide more accurate prognosis. There is a need for biomarkers that can characterise the diversity of the cancer, and perhaps in the future, some of these biomarkers can point to targets for use in targeted and personalised medicine. The introduction of next generation sequencing (NGS) has allowed researches to sequence thousands of genes at a time through fast and relatively inexpensive whole exome and genome sequencing. The challenge with these enormous amounts of data is to extract relevant clinical information. In this review, we systematically evaluate all the published literature on the use of NGS of genomic DNA in HNSCC.