The management of gastrointestinal stromal tumors (GISTs) has been revolutionized in recent years by two major developments: the introduction of imatinib mesylate as a targeted therapeutic agent and the dramatic change in the tumor metabolic activity following successful therapy making in fluorodeoxyglucose (FDG)-PET as the modality of choice for monitoring therapeutic response. In the present communication, we have explored the current role of PET/computed tomography (CT) imaging in GIST on the basis of a brief overview of the published studies and our experience on the subject gained in a large tertiary care setting. There is now convincing evidence that serial PET study is more sensitive and reliable for determining treatment response to imatinib mesylate in patients of GIST, when compared with only conventional CT monitoring. This modality also appears to be of potential value in initial disease evaluation including prediction of malignant potential in recently diagnosed GIST and in selection of optimal dose of imatinib for therapy. The findings of detection of disease recurrence on discontinuing imatinib and acquired resistance to imatinib provide insight into the issue of therapeutic endpoint definition. On the basis of the experience gained in recent times, the future potential of this powerful modality in this setting is hypothesized.