The myelin-associated glycoprotein (MAG) is a 100-kD, integral membrane glycoprotein that is a member of the immunoglobulin superfamily and appears to function in interactions between myelin-forming cells (both oligodendrocytes and Schwann cells) and the axolemma. Its early loss in the development of multiple sclerosis plaques in comparison to other myelin proteins suggests that it could play a key role in the pathogenesis of this disease. This selective loss of MAG may relate to the high susceptibility of human MAG to cleavage by a Ca2+-activated neutral protease. Human MAG also contains a highly immunogenic carbohydrate determinant that is also expressed on other neural glycoconjugates and is the antigen recognized by many human IgM paraproteins that occur in patients with peripheral neuropathy. This article emphasizes the role of MAG in multiple sclerosis and peripheral neuropathies occurring in association with IgM paraproteinemia.