Abstract The human brain requires continual oxygen delivery to meet its enormous metabolic demand, and suffers devastating consequences when this oxygen supply is disrupted, as in stroke. While new endovascular treatments have shown promise to improve cerebrovascular outcomes, they are hampered by the lack of noninvasive biomarkers to stratify patients who are good candidates for these therapies. In particular, imaging of oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) is a long- recognized but unmet need in the stroke community. This project develops novel, clinically feasible tools for non-invasive oxygenation imaging, to study how the brain dynamically meets its oxygen needs and identify key pathophysiology in neurological patients. Our specific aims are (1) to enhance MRI-based reconstructions of OEF maps through novel “fingerprint matching” to microvascular voxel simulations and validation with the [15O]-oxygen gas PET reference; and (2) to develop a hybrid PET and MRI approach to rapidly image CMRO2 dynamics and its functional networks during a single resting scan. The novelty of this work lies in leveraging the unique capabilities of simultaneous PET/MRI scanners. The use of a PET/MRI system to validate and augment MRI-only methods for clinical OEF assessment with simultaneous PET scans is highly innovative. Hybrid measurements also allow for new, rapid CMRO2 imaging approaches that embody the best of each modality – fast and quantitative – to model brain functional connectivity and disease. Success of this proposal will generate novel neuroimaging tools to study brain oxygen consumption that are broadly applicable to any site with an MRI scanner. These advancements will enable use of physiological imaging biomarkers to evaluate endovascular therapies and reduce stroke risk, and enhance our fundamental neuroscience capabilities to understand the vascular underpinnings of brain function.