Concerning diet-induced thermogenesis, methodological issues relate mainly to the interpretation of measurements, rather than to the technical methodology as such. In the following, we point to a series of issues where the analysis often suggests the occurrence of UCP1-related diet-induced thermogenesis but where the observations are often the consequences of a process that has induced leanness rather than being the cause of them. We particularly emphasize the necessity of focusing on the total organism when interpreting biochemical and molecular data, where the concept of total tissue values rather than relative data better reflects physiologically important alterations. We stress the importance of performing experiments at thermoneutrality in order to obtain clinically relevant data and stress that true thermogenic agents may be overlooked if this is not done.