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Abstract Gastrointestinal stromal tumour is now recognized as a distinct pathological malignancy and has received much attention over the last few years. Despite almost universal resistance to chemotherapy, a novel therapy, Imatinib, which targets the KIT receptor, has changed the natural history of this disease. We have audited the first 26 consecutive patients with gastrointestinal stromal tumour treated over 4 years at a single institution. A practical guide to the management of common toxicities and drug resistance is reported with a review of the published reports. Many of the strategies used are likely to be widely applicable to the use of targeted therapies in other malignancies.