Traditional anatomic tumor response criteria are based on uni- or bidimensional changes in tumor size, and do not take into account changes in tumor metabolism, tumor density, or decrease in the number of intratumoral vessels. These changes are, however, all indicative of response to imatinib therapy in patients with gastrointestinal stromal tumor (GIST). In these patients, metabolic responses seen on positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose (18FDG) have been shown to be closely related to clinical benefit. Furthermore, these metabolic changes precede by weeks or months significant decrease in tumor size on computed tomography (CT). Conversely, lack of metabolic response on FDG-PET indicates primary resistance to the drug and may help identify patients who would benefit from another therapy, while re-emergence of metabolic activity within tumor sites following a period of therapeutic response indicates secondary resistance to the drug. Newly proposed CT criteria using either no growth in tumor size or a combination of tumor density and size criteria have shown a close correlation with the predictive value results of FDG-PET. Thus, the integration of FDG-PET and CT, as in the combined hybrid PET/CT scanners now available, will not only optimize the evaluation of patients with GIST treated with molecularly targeted drugs, but may ultimately help shorten clinical trials, and accelerate drug development in this disease and other cancers as well.