Gastrointestinal stromal tumour (GIST) is a rare tumour. Historically, surgery has been the only effective treatment. The prognosis of patients with gastrointestinal stromal tumour is poor. Even after apparently 'curative' surgical resection more than 50% of patients relapse. The development of an effective novel targeted therapy against GIST (imatinib mesylate) is a success story of molecular biology that has dramatically altered the management of patients with these tumours. However, as follow up of patients who have initially responded to imatinib has increased, it has become evident that such hopes of cure were premature because responses to imatinib are of limited duration. Unresolved issues include the role of imatinib as an induction (neo-adjuvant) therapy prior to surgery, or as adjuvant treatment after surgery, the role of surgery in patients with a differential or partial response and the role of surgery in patients with isolated metastatic disease. In the present paper the biology and natural history of GIST are reviewed, and the complexities of surgical management that exist in the context of an effective, but not curative, biological therapy, are addressed.