The outcome for patients with head and neck squamous cell carcinoma remains poor, despite improvements in diagnosis and treatment over the past three decades. This has triggered great interest in the genetic events that underpin the aetiology and clinical behaviour of this group of cancers. As a result, the genetic profile for head and neck squamous cell carcinomas at different sub-sites has been relatively well characterised at the chromosomal level. Various studies have shown links between specific aberrations in head and neck squamous cell carcinoma and clinical outcome, e.g. loss of heterozygosity at 2q and 18q is commonly associated with poor prognosis, and loss of heterozygosity at 9p21 is associated with recurrence. However, there is as yet no significant clinical application of this genetic knowledge as regards the screening, diagnosis or treatment of head and neck squamous cell carcinoma. Here, we summarise the current state of knowledge, and highlight the most promising areas of research that may facilitate the translation of genetic data into clinical benefit.