While oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are fundamental parameters of brain health and function, a robust MRI‐based mapping of OEF and CMRO2 amenable to functional MRI (fMRI) has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity‐selective spin labeling to isolate MR signal exclusively from postcapillary venular blood on a voxel‐by‐voxel basis. Measuring the T2 of this venular‐targeted blood allows calibration to venular oxygen saturation (Yv) via theoretical and experimental T2 versus blood oxygen saturation relationships. Yv is converted to OEF, and baseline CMRO2 is subsequently estimated from OEF and additional cerebral blood flow and hematocrit measurements. Theory behind the QUIXOTIC technique is presented, and implications of cutoff velocity (VCUTOFF) and outflow time parameters are discussed. Cortical gray matter values obtained with QUIXOTIC in 10 healthy volunteers are Yv = 0.73 ± 0.02, OEF = 0.26 ± 0.02, and CMRO2 = 125 ± 15 μmol/100 g min. Results are compared to global measures obtained with the T2 relaxation under spin tagging (TRUST) technique. The preliminary data presented suggest that QUIXOTIC will be useful for mapping Yv, OEF, and CMRO2, in both clinical and functional MRI settings. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.