Combining chemotherapy with radiotherapy has resulted in significant clinical improvements in many different tumour types. However, the non-specific mechanisms by which these drugs exert their effects mean that this is often at the expense of increased side effects. Previous attempts at using targeted drugs to induce more tumour specific radiosensitisation have been generally disappointing. Although cetuximab, an EGFR monoclonal antibody, resulted in improved overall survival in HNSCC when combined with radiotherapy, it has failed to show benefit when added to chemo-radiotherapy. In addition, our inability to successfully use drug treatments to reverse tumour hypoxia is underlined by the fact that no such treatment is currently in widespread clinical use. The reasons for these failures include the lack of robust biomarkers, and the previous use of drugs with unacceptable side-effect profiles. Despite these disappointments, there is reason for optimism. Our improved understanding of key signal transduction pathways and of tumour specific DNA repair deficiencies has produced new opportunities to specifically radiosensitise tumours. Novel strategies to reduce tumour hypoxia include the use of drugs that cause vascular normalisation and drugs that reduce tumour oxygen consumption. These new strategies, combined with better compounds at our disposal, and an ability to learn from our previous mistakes, mean that there is great promise for future drug-radiotherapy combinations to result in significant clinical benefits.