Several areas of research have contributed to the establishment of a paradigm that meets the requirements for the selective uptake of essential polyunsaturated fatty acids (EPUFA) into brain. First, discrete studies have demonstrated that cholesterol and the nonessential fatty acids, (palmitic, oleic, stearic) do not enter the brain parenchyma. These studies demonstrated that the 18 carbon-monocarboxylic fatty acids, linoleic acid with two cis-double bonds entered brain, whereas oleic acid, with one cis-double bond, did not enter brain. It was concluded the entry of essential fatty acids into brain is accomplished in a highly selective and discrete manner. Further, the typical blood-borne lipoproteins do not traverse the endothelial cells of the capillary network and enter into the brain, otherwise cholesterol, palmitic, oleic, and stearic acids from blood would be located within brain. Second, several investigators have shown that the endothelial cells of the capillary network contain lipoprotein receptors, yet one conclusion is that the brain does not utilize low-density lipoprotein (LDL)-cholesterol. Third, recently, the existence and function of a significant number of distinctive trans-membrane monocarboxylic acid transporters, (MCTs) and fatty acid transport proteins (FATPs) have been described. No transporters have been described to date with the specificity necessary to transfer only EPUFA into brain. A blueprint with the minimal elements for delivery and selectivity is proposed. Lipoproteins enter the endothelial cells because the lipoprotein receptors are positioned on their luminal membrane. Essential fatty acid transporter(s) are positioned on the abluminal membrane of these endothelial cells to allow for the entry of EPUFA into brain. Within the endothelial cell there is opportunity for lipid management and transformation such that EPUFAs are selectively culled for delivery to the essential fatty acid transporter(s), which facilitates their transfer into brain.