Nature Reviews Clinical Oncology, Published online: 10 June 2026; doi:10.1038/s41571-026-01161-yTraditional radiotherapy approaches involve the delivery of a uniform radiation dose to the entire tumour. Despite considerable effectiveness, this approach comes with the limitations of a lack of activity against larger tumour volumes as well as off-target irradiation of surrounding non-malignant tissues. Spatially fractionated radiotherapy, involving deliberate non-uniform irradiation, has the potential to address these challenges, with early data suggesting safety and activity in patients with advanced-stage cancers. In this Review, the authors describe the emerging role of spatially fractionated radiotherapy in the management of patients with cancer.