Current algorithms for the clinical management of patients with squamous cell carcinoma of the head and neck (HNSCC) are based on a stage-dependent strategy where all patients at the same TNM stage receive the same treatment. Patient outcomes might be substantially improved by biomarker-guided treatment selection based on individual differences in the genetic and biological characteristics of tumours. Rapid technical advances enabling fast and affordable comprehensive molecular characterisation of tumours have led to increased knowledge of the molecular pathways involved in neoplastic transformation and disease progression in HNSCC. Despite notable successes in other tumour entities, the exploitation of molecular data for the improvement of tumour staging, prognosis, and individual treatment selection for patients with HNSCC has not yet become clinical routine. In this Review, we discuss and merge existing and new information on prognostic biomarkers for HNSCC, with the potential to improve clinical management of patients in the near future.