(18)F-FDG PET and, more recently, PET/CT have been established as response biomarkers for monitoring cytotoxic or cytoreductive cancer therapies. With the advent of targeted cancer therapies, which are predominantly cytostatic, (18)F-FDG PET is increasingly being used to monitor the therapeutic response to these agents as well. The impressive outcome of (18)F-FDG PET studies in patients with gastrointestinal stromal tumors treated with imatinib mesylate brought to the forefront the use of this biomarker for assessing the response to targeted therapies. The use of (18)F-FDG PET for this purpose has practical challenges, including quantitative analysis and timing of scans. This review provides a summary of clinical studies of targeted therapies done to date with (18)F-FDG PET and provides guidance on practical issues to ensure the optimal interpretation of imaging data in drug development and for patient care.