The perfusion of rat brain with 125I-transferrin resulted in a receptor-mediated uptake of transferrin into the endothelium of the blood-brain barrier followed by its detection in the brain. During a pulse-chase experiment, 125I-transferrin accumulated in the endothelial cells during the pulse, with a decrease of this intraendothelial radioactivity during the chase associated with a concomitant increase in the nonvascular elements of the brain. The receptor-mediated movement of transferrin across the blood-brain barrier suggests that the brain may derive its iron through the transcytosis of iron-loaded transferrin across the brain microvasculature. We discuss the likelihood that aluminum and other potentially toxic heavy metals, which also bind tightly to transferrin, may enter the brain by this pathway. We also discuss the possibility that other large molecules including neuroactive peptides and neurotrophic viruses may enter the brain through a similar receptor-mediated, vesicular transcytotic route.