A plethora of aberrations are associated with progress and outcome for head and neck cancer patients and some have been shown to provide prognostic information independent of the TNM staging system. These findings justify future studies that will harness recent advances in technologies to refine the range of molecular markers available. Important lessons have been learnt during the last two decades, particularly the need to perform multivariate analysis and to combine information derived from several molecular markers. At present the overall evidence is insufficient to alter clinical practice or to consider restricting clinical trials of new adjuvant to subsets of patients, identified on the basis of the use of molecular markers. However, a number of key prospective clinical studies are in progress and we can be optimistic that in the near future clinical research incorporating specific markers may provide new criteria for defining risk of relapse or of developing a new primary tumour, and guide the choice of optimal adjuvant treatment after surgery. The only way to truly validate a marker is to incorporate it into large clinical trials, and it is anticipated that the new treatment options that are on the horizon, that are likely to be an improvement on radiotherapy alone, will provide opportunities to help translate this laboratory research into clinical practice.