In this review, we describe the current approaches used for quantitative assessment of regional and global function with positron emission tomography (PET) imaging (combined with structural imaging modalities) with emphasis on both research and clinical applications of this powerful approach. We particularly refer to the impact of such measurements in assessing physiological processes such as aging and measuring response to treatment in serious disorders such as cancer. Although a multitude of methods has been described in literature, the optimal approaches that are both accurate and practical in clinical settings need to be defined and refined. Standardized uptake value (SUV) continues to be the most widely used index in the current practice. Calculating SUV at a single time point and assigning standard regions of interest are inadequate and suboptimal for the purposes adopted by the medical community. The concepts of partial volume correction for measured values in small lesions, dual-time point and delayed PET imaging, and global metabolic activity for assessment of various stages of disease may overcome deficiencies that are associated with the current quantitative (ie, SUV) techniques. Serious consideration of these concepts will enhance the role and reliability of these quantitative techniques, and therefore compliment the World Health Organization or the Response Evaluation Criteria in Solid Tumors (RECIST) criteria for managing patients with cancer and other disorders, including physiological states such as aging and serious diseases such as atherosclerosis and neurological diseases. We also introduce the concepts that allow for segmentation of various structural components of organs like the brain for accurate measurement of functional parameters. We also describe complicated kinetic modeling and methodologies that have been used frequently for assessing metabolic and pharmacological parameters in the brain and other organs. Simplified quantitative techniques based on these concepts are described, but should be validated against the kinetic models to test their role as practical tools.