We describe methods and issues that are relevant to the measurement of change in tumor uptake of (18)F-fluorodeoxyglucose (FDG) or other radiotracers, as measured from positron emission tomography/computed tomography (PET/CT) images, and how this would relate to the establishment of PET/CT tumor imaging as a biomarker of patient response to therapy. The primary focus is on the uptake of FDG by lung tumors, but the approach can be applied to diseases other than lung cancer and to tracers other than FDG. The first issue addressed is the sources of bias and variance in the measurement of tumor uptake of FDG, and where there are still gaps in our knowledge. These are discussed in the context of measurement variation and how these would relate to the early detection of response to therapy. Some of the research efforts currently underway to identify the magnitude of some of these sources of error are described. In addition, we describe resources for these investigations that are being made available through the Reference Image Database for the Evaluation of Response project. Measures derived from PET image data that might be predictive of patient response as well as the additional issues that each of these metrics may encounter are described briefly. The relationship between individual patient response to therapy and utility for multicenter trials is discussed. We conclude with a discussion of moving from assessing measurement variation to the steps necessary to establish the efficacy of PET/CT imaging as a biomarker for response.