Objective: The main aim of this article was to review the clinical and biological factors that have been shown to influence the response of the head and neck squamous cell carcinoma (HNSCC) to primary radiotherapy and briefly discuss how some of these factors could be exploited to improve outcome. Design: Medline based search covering 1982-2006 to identify the HNSCC literature where the effect of clinical and biological factors on locoregional control and overall survival were investigated. Results: Clinical factors are routinely used in management decisions. Nevertheless, identically staged tumours receiving the same treatment may have different outcomes. Biological factors such as hypoxia, proliferation and radio-sensitivity play an important role in radiation response. However, these are not currently used in practise because tests that are clinically reliable and feasible are not available. Conclusion: High-quality translational research will allow us to develop biological tests that can be used in routine clinical practise to tailor individual treatment, with the ability to improve patient outcome further by modifying the underlying tumour biology. © 2007 The Authors.