Abstract: Sortilin was discovered in 1997 by Petersen and his colleagues. The single transmembrane receptor was isolated as a 95 kDa membrane glycoprotein by receptor-associated protein affinity chromatography and therefore initially named gp95. The cDNA library screening revealed sequence homology between the luminal segment of gp95/sortilin and the yeast vacuolar sorting protein 10 protein (Vps10p) domain  (Petersen et al., 1997). The Vps10p domain was first identified in the Saccharomyces cerevisiae protein Vps10p that directs lysosomal enzymes from the Golgi to the vacuole (Marcusson et al., 1994). The trafficking path is even more complex for the mammalian Vps10p domain receptors that can shuttle between vesicles in the endo-lysosomal system and the cell (Nielsen et al., 2001). The Vps10p domain is evolutionary conserved and has a unique 10-bladed β-propeller structure (Quistgaard and Thirup, 2009). In mammalians, five receptors with Vps10p domains have been reported: sortilin (also known as neurotensin receptor 3), sortilin-related receptor central nervous system expressed 1, 2, and 3 (SORCS1, SORCS2, SORCS3), and sorting protein-related receptor with A-type repeats (SORLA; also known as LR11 and SORL1). The members of this gene family are collectively known as Vps10p-domain receptors or simply sortilins. They are all type-1 transmembrane receptors with a short cytoplasmatic tail and a large extracellular domain. The cytoplasmatic domain contains sorting motifs for specific adaptor proteins that direct intracellular trafficking. The Vps10p domain is located on the extracellular part that is the place for protein binding. Sortilin has this basic structure, while the other receptors have additional motifs (Figure 1A), indicating a more comprehensive target-recognition profile (Willnow et al., 2008). The sortilins are involved in several physiological functions of the cells and are therefore characterized as multifunctional receptors. Sortilin acts as a receptor or co-receptor in endocytosis, cell survival, signal transduction and directs proteins such as neurotrophins. Similarly, SORLA sorts different kinases, phosphatases, and signaling receptors to their correct intracellular location. SORLA is also a receptor for apolipoprotein E in the brain and is involved in processing amyloid precursor protein. SORCS1 and SORCS3 regulate energy homeostasis as intracellular trafficking receptors for tropomyosin-related kinase B. Furthermore, SORCS1 participate also in amyloid precursor protein processing and insulin secretion in the pancreas. SORCS2 is a co-receptor for proneurothrophins and contributes to producing the oxygen species scavenger glutathione under oxidative stress in neurons. A complete list of sortilins’ binding partners can be found in a more recent review (Malik and Willnow, 2020). Sortilins are expressed throughout the central and the peripheral nervous system in defined cell populations (Willnow et al., 2008). Accordingly, they have mainly been investigated in neurons and glial cells, but their role in the cells of the blood-brain barrier (BBB) has been completely neglected until now.