Modern functional neuroimaging techniques, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and optical imaging of intrinsic signals (OIS), rely on a tight coupling between neural activity and cerebral blood flow (CBF) to visualize brain activity using CBF as a surrogate marker. Because CBF is a uniquely defined physiological parameter, fMRI techniques based on CBF contrast have the advantage of being specific to tissue signal change, and the potential to provide more direct and quantitative measures of brain activation than blood oxygenation level-dependent (BOLD)- or cerebral blood volume (CBV)-based techniques. The changes in CBF elicited by increased neural activity are an excellent index of the magnitude of electrical activity. Increases in CBF are more closely localized to the foci of increased electrical activity, and occur more promptly to the stimulus than BOLD- or CBV-based contrast. In addition, CBF-based fMRI is less affected by confounds from venous drainage common to BOLD. Animal studies of brain activation have yielded considerable insights into the advantages of CBF-based fMRI. Based on results provided by animal studies, CBF fMRI may offer a means of better assessing the magnitude, spatial extent, and temporal response of neural activity, and may be more specific to tissue state. These properties are expected to be particularly useful for longitudinal and quantitative fMRI studies. J. Magn. Reson. Imaging 2005. Published 2005 Wiley-Liss, Inc.