The blood-brain barrier to the protein horseradish peroxidase (HRP, tool. wt. 40 000) is the consequence of both an obstruction to passive extracellular movement and the absence of an active transcellular migration. Although the endothelium of some cerebral arterioles can transfer protein from blood to perivascular basement membrane by means of vesicles, the endothelium of cerebral capillaries cannot. The barrier may be passed when the junctions between endothelial cells become patent as in some brain tumors and in vitally- induced choroid plexus papillomas. The vessels in the latter tumors also have fenestrae and numerous endothelial pits and vesicles, features that may also account for the increased permeability of the tumor vessels. The barrier is also opened by infusing hyperosmotic non-electrolytes into the internal carotid artery. Within 60 sec after the infusion of 1.4 M-arabinose into one carotid artery of adult rats that had received HRP intravenously, the vessels on the infused side of the brain extravasate peroxidase. The escape of HRP is probably through junctions or actively formed channels and not by means of vesicular transport. When hyperosmotic arabinose is injected first, the brain fixed and then, 1 hr after fixation, HRP is infused into the aorta, perivascular exudates appear primarily on the saccharide-infused side of the brain. Since vesicular transfer requires energy and is halted by chemical fixation, the protein must have crossed the endothelium through pre-existing channels. Comparable to the effects of hyperosmotic urea on the vessels of the rabbit brain, only a few endothelial junctions were obviously patent. It is likely, therefore, that most of the passage is by way of channels formed, perhaps, by confluent vesicles. The channels, once formed, do not close im- mediately but remain patent long enough to be fixed in the open position. Neurons deep within the brain stem are inaccessible to protein circulating within capillaries immediately adjacent to them. The same neurons, however, can pinocytose HRP at their axon terminals which innervate peripheral organs such as muscle and mucous membrane. The blood vessels of these tissues are permeable to protein which, upon crossing the vessels, are incorporated by the axon terminals and transported within the axons back to lysosomes within the neuronal soma. In this way, large molecules circulating in the systemic blood may enter certain neurons even though the same molecules are barred from crossing the cerebral capillaries supplying these neurons. In contrast to hydrophilic molecules, there is no appreciable restriction to the passage of lipids from blood to brain. Fatty acids (FA) injected into blood are directly incorporated into cerebral lipids. When large concentrations of the polyunsaturated FA linolenic acid, wbich is strongly osmiophilic, is infused into one carotid artery, the soap droplets formed fuse with endothelial cell membranes. The osmiophilic droplets enter the endothelium and penetrate cytomembranes as well as cell membranes except, perhaps, for the inner nuclear membrane; droplets readily enter the perinuclear cistern but are never found within the nucleus of any cell, be it endothelial, smooth muscle, epithelial or neuronal. Some of the FA enters endothelial pits and vesicles and may represent that fraction of the FA which normally circulates as a complex with serum albumin. Mitochondria are infiltrated by droplets as are synaptic vesicles and axoplasm of perivascular and intracerebral neurons.