The coupling of brain cell function to the vascular system is the basis for a number of functional neuroimaging methods relevant for human studies. These include methods as diverse as functional magnetic resonance imaging, positron emission tomography, single photon emission tomography, optimal intrinsic signals, as well as near infrared spectroscopy, a method that may have imaging capabilities in the near future. These methods map a specific localized brain activation through a vascular response, such as an increase in cerebral blood flow or a change in blood oxygenation. To understand these direct maps to obtain high resolution maps of localized functional brain activity, a precise knowledge of the specific underlying physiological mechanisms and methodological properties and restrictions is essential. In this article, these fundamental physiological and methodological aspects will be discussed. After reviewing how the techniques cited obtain maps of functional activity, we will discuss our current knowledge of the physiology of coupling with particular reference to the functional imaging techniques. Specifically, we will consider the function, the mediators, and the hemodynamic mechanisms of coupling and point out potential interference by diet, and neurological disease.