Following an historical review of earlier attempts to develop separated head and brain preparations and their contributions to modern-day understanding of the neurophysiology and neurochemistry of the central nervous system, the experiments that eventually led to the first successful total isolation of the mammalian brain are presented. The operative strategies emphasizing the anatomical and physiological problems requiring solution that resulted in vascular and neurogenic separation from the parent body and cephalon are described. The innovative engineering concepts that were utilized in the design of miniaturized equipment to maintain the isolated brain in a living state under conditions of cross circulation, extracorporeal artificial perfusion and transplantation are elaborated. Investigations employing isolated brain and cephalic preparation documenting tissue substrate requirements, metabolic and rheological conditions prevailing at various low temperatures and the immunologically privileged state of the separated organ are briefly presented. The unique opportunities these isolated brain models offer for study are emphasized as well as the complexity of their surgical preparation, which, to date, has limited their universal applications.