Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named naturally occurring autoantibodies (NAbs). NAbs may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. Accumulating evidence indicates that naturally occurring antibodies can act as systemic surveillance molecules, which tag, damaged or stressed cells, invading pathogens and toxic cellular debris for elimination by the immune system. In addition to acting as detecting molecules, certain types of NAbs actively signal in different cell types with a broad range of responses from induction of apoptosis in cancer cells to stimulation of remyelination in glial cells. This review emphasizes functions and characteristics of NAbs with focus on remyelination-promoting mouse and human antibodies. Human remyelination-promoting NAbs are potential therapeutics to combat a wide spectrum of disease processes including demyelinating diseases like multiple sclerosis. We will highlight the identified glycosphingolipid (SL) antigens of polyreactive remyelination-promoting antibodies and their proposed mechanism(s) of action. The nature of the identified antigens suggests a lipid raft-based mechanism for remyelination-promoting antibodies with SLs as most essential raft components. However, accumulating evidence also suggests involvement of other antigens in stimulation of remyelination, which will be discussed in the text.