This chapter discusses head and neck cancers, and covers the epidemiology and molecular biology of head and neck cancer. Head and neck cancer is a heterogeneous disease and most commonly caused by tobacco and alcohol use, as well as high-risk human papillomavirus (HPV) infection. HPV-negative and -positive HNSCC are demographically, biologically and clinically distinct entities with more favourable outcomes associated with HPV-positive tumours of the oropharynx. Comprehensive genomic analyses show that more functional loss of tumour suppressors are present in HPV-negative tumours compared to HPV-positive tumours. Furthermore, HNSCC can be molecularly characterized into five subtypes. The challenges facing future investigations are efficient translation of these biological findings into clinically meaningful advancements in patient treatment.