In patients with carcinoma of the head and neck and of the esophagus, metabolic and functional imaging by PET with (18)F-FDG has a pivotal role in the evaluation of tumor response to therapy, specifically, in the prediction of progression-free survival and overall survival. Metabolic imaging allows the detection of biochemical changes within tumor cells as opposed to identifiable morphologic changes. Anatomic imaging modalities do not reliably differentiate between responders and nonresponders early during the course of follow-up. The correlation between histopathologic tumor response after preoperative therapy and clinical prognosis is well established for many cancers. Squamous carcinoma of the head and neck and esophageal carcinoma demonstrate avid (18)F-FDG uptake. For these cancers, (18)F-FDG PET parallels histopathologic findings in its ability to detect residual viable tumor; therefore, it is a valuable tool for the noninvasive assessment of histopathologic tumor response in advanced-stage cases after neoadjuvant therapy before surgery. Early determination of nonresponders is of prime importance, as timely therapy modification can be accomplished for patients who do not demonstrate a response to therapy. This determination is exceptionally important for head and neck and esophageal malignancies, both of which are known for their unfavorable prognosis, as early modifications in therapy regimens for nonresponders may improve patient outcome. There is now evidence that (18)F-FDG PET is a sensitive and specific method for determining therapy response and for providing important prognostic information for these cancers. Therefore, (18)F-FDG PET may change patient management and lead to improved survival for a selected group of patients with carcinoma of the head and neck and of the esophagus.