This chapter reviews the development of positron-labeled brain perfusion agents. Significant progress has been made in the development of new positron-emitting radiopharmaceuticals for regional cerebral blood flow (rCBF) measurements, as well as for evaluating cerebral metabolism, mapping neuroreceptors, imaging breast tumors, etc. It is easy to overlook the possibility of rapid in vivo metabolism of a radiolabeled compound when one is considering the development of any new radiopharmaceutical. Only a few positron-emitting volatile radiopharmaceuticals have been prepared and evaluated for use as rCBF agents. Oxygen-15 labeled water was one of the first tracers suggested for use as an rCBF agent and remains today the most widely used positron-emitting rCBF agent. Antipyrine was an alternative agent in rCBF measurements to avoid the technical problems associated with the use of a volatile tracer. Cyclotrons provide a reliable source of positron-emitting radionuclides, and often, they provide the only practical source of large quantities of these radionuclides.