The short half-life of 15O led early observers to believe that it was unsuitable for use as a biological tracer. However, initial studies with this nuclide demonstrated its potential usefulness for in vivo, regional physiologic measurements. Subsequently, techniques were developed to measure cerebral blood flow (CBF), blood volume, and oxygen metabolism using intracarotid injection of 15O-labeled radiopharmaceuticals and highly collimated scintillation probes to record the time course of radioactivity in the brain. The development of positron emission tomography (PET) made possible the in vivo, noninvasive measurement of the absolute concentration of positron-emitting nuclides. A variety of tracer kinetic models were formulated to obtain physiologic measurements from tomographic images of the distribution of 15O-labeled radiopharmaceuticals in the brain. 15O-labeled carbon monoxide, administered by inhalation, binds to hemoglobin in RBCs, and therefore can be used as a intravascular tracer to measure regional cerebral blood volume (rCBV). Several strategies have been developed to measure regional CBF using 15O-labeled water as an inert, diffusible flow tracer. Regional cerebral oxygen metabolism is measured using scan data obtained following the inhalation of 15O-labeled oxygen; independent determinations of local blood flow and blood volume are also required for this measurement. The tracer kinetic models used to measure rCBV, blood flow, and oxygen metabolism will be described and their relative advantages and limitations discussed. Several examples of the use of 15O tracer methods will be reviewed to demonstrate their widespread applicability to the study of cerebral physiology and pathophysiology.