Cellular repopulation is one of the most important biological determinants of the clinical outcome of fractionated radiation therapy. A number of randomized controlled trials of altered dose-fractionation have been conducted in patients with squamous cell carcinoma of the head and neck (HNSCC) and the main biological lessons from these are summarised. Data for other tumour histologies are relatively sparse. Further progress in radiotherapy for HNSCC is unlikely to result from altered fractionation alone, but a number of novel strategies for overcoming or exploiting repopulation are being researched. In the next 5 years, the top priorities for clinical and translational research in this field should be the development of clinically applicable predictive assays, functional imaging as an aid to optimize the dose distribution, optimization of combined modality therapies and novel biological strategies specifically targeting tumour cell proliferation.