Gastrointestinal stromal tumours (GIST) are a relatively rare, but well characterised clinical entity. This tumour is defined by a predominantly spindle-cell morphology and its pathobiology by the presence of Kit (receptor tyrosine kinase). The majority of GIST have a gain of function mutation in an exon hot spot that leads to constitutive activation of Kit, promoting proliferation and anti-apoptotic signalling. Imatinib mesylate (Gleevec), Glivec, Novartis) is a specific inhibitor of Kit kinase activation and in Phase II clinical trials, it has proven to be remarkably effective in heavily pre-treated patients with advanced GIST. Molecular determinants of response and resistance are the subject of ongoing investigations. Additionally, clinical trials are underway to explore the use of imatinib mesylate in the adjuvant setting. These initial evaluations with imatinib mesylate provide proof of concept for hypothesis driven, rational drug design of selective signal transduction inhibitors in the management of solid tumour malignancies.