The possibility of an autoimmune mechanism of pathogenesis in amyotrophic lateral sclerosis has long been considered, but the evidence to support a conventional autoimmune process, reviewed here, is inconclusive. However, antibodies that react in vitro with gangliosides have recently been found in sera of a large majority of patients with classical amyotrophic lateral sclerosis and other motor neuron syndromes. A working hypothesis is proposed, suggesting how antibodies might be related to the disease process. The hypothesis attempts to account for (1) a pathogenic role of antibodies directed against the carbohydrate components of glycolipids, (2) the selectivity of the process for motor neurons, (3) an antibody-mediated mechanism that could result in apparently degenerative neuropathological changes without signs of inflammation, and (4) a type of autoimmune response that is extremely difficult to suppress by conventional means. Although the evidence for this hypothesis is by no means complete, its critical features are all testable.