An important biological consequence of the initial interactions between the cell surface and its extracellular environment is the diversity of cellular responses ranging from overt repulsion or avoidance reaction to stable adhesion or final positioning. It is now evident that positive and negative guiding mechanisms are equally relevant to normal pattern formation during development and decisive for the outcome of a regenerative process. In this context, the present review summarizes the knowledge about the extracellular matrix glycoprotein tenascin-R, a member of the tenascin gene family. In contrast to all other known family members, tenascin-R is exclusively expressed in the central nervous system of vertebrates by oligodendrocytes and neuronal subsets at later developmental stages and in adulthood. We focus on the glycoprotein's structure, tissue distribution and functional implications in the molecular control of axon targeting, neural cell adhesion, migration and differentiation during nervous system morphogenesis and pathology.