Project Summary PET and MRI offer complementary views of physiology and the ability to measure data from both modalities concurrently provides a unique opportunity to study biological mechanisms in ways that were heretofore impossible to realize in intact animals, including human subjects. However, this advance in hardware and data acquisition poses new challenges for data analysis and interpretation due to the fact that the modalities are based upon different physical principles and generally reflect different in vivo phenomena. Conceptually, we address the problem and seize the opportunity via integrated PET/MR analysis frameworks wherein shared physiological mechanisms mathematically link quantitative PET and MR models, improving the accuracy and precision of physiological measurements and, in several instances, permitting outcomes not achievable using either modality alone. This general approach is proposed for development in several specific and illustrative cases – neurotransmission, mitochondrial membrane potential, and oxidative stress – that together span diverse organ systems, physiological processes, and potential disease applications.