The reliability of established anatomical imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), is compromised in following response to certain types of treatment if metabolic improvement occurs before morphologic change is apparent. Thus, traditional imaging techniques cannot discriminate early tumor response because they are based on purely visual structural assessments. Recently, the use of positron emission tomography (PET), most commonly employing the radiotracer 18F-fluoro-2-deoxy-D-glucose (FDG), has been shown to improve the assessment of tumor behavior by highlighting early functional changes in tumor glucose metabolism that appear to correlate closely with metabolic tumor response to imatinib mesylate. Like CT and MRI, PET can identify an abnormal mass; its improvement over these techniques lies in its ability to differentiate active tumor from necrosing tissue, malignant from benign tissue, and recurrent tumor from scar tissue. Understanding and using this tool should improve our ability to accurately follow response in GIST patients treated with imatinib mesylate, and permit this new therapeutic approach to be used optimally with accurate follow-up assessments and informed therapeutic decision-making.