Exploration of the molecular landscape of head and neck cancers utilising next generation sequencing has confirmed previously known HNSCC genome alterations such as mutations in TP53, CDKN2A, PIK3CA, PTEN, and HRAS, but also identified novel genes such as NOTCH1, XRCC1, and RAD51C. While TP53 mutations are the most common genetic alterations in HNSCC, inactivation of p16 continues to be an important target in HPV-positive tumours, while exploration of DNA damage repair genes and synthetic lethality is emerging as a promising approach in combating HPV-negative tumours. This evidence concerns the gene NOTCH1 and head and neck squamous cell carcinoma.