Gangliosides are major molecular structures on the surfaces of all vertebrate nerve cells and axons. Defined as sialic-acid bearing glycosphingolipids, gangliosides are found on all vertebrate tissues, but are predominant sialoglycoconjugates in the central and peripheral nervous systems. Two of the quantitatively major brain gangliosides, GD1a and GT1b, are complementary ligands for myelin-associated glycoprotein (MAG), a cell-cell recognition protein enriched on the innermost wrap of myelin membranes, apposed to the axon surface. MAG, on myelin, binding to gangliosides, on axons, has been proposed to enhance long-term axon-myelin stability and inhibit axon regeneration. In support of these hypothesis, mice engineered to lack complex gangliosides display central and peripheral nervous system axon degeneration, myelination defects, and progressive motor behavioral and neurological deficits similar to those of Mag-null mice. A related congenital mutation in a ganglioside biosynthetic enzyme in humans results in severe seizures and neurological degeneration in affected children. In addition to supporting long-term axon-myelin stability, MAG is a major myelin-derived inhibitor of axon regeneration in the injured adult nervous system (along with Nogo, oligodendrocyte-myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans). Evidence indicates that the inhibitory effect of MAG is mediated by two classes of receptors, the glycosyl-phosphatidylinositol anchored Nogo receptor (NgR) and gangliosides GD1a and GT1b.