The cause of amyotrophic lateral sclerosis is unknown. In this review clinical and scientific data that are pertinent to understanding this disease are reviewed. There are currently several major controversies concerning the possible role of immunological factors, genetic factors, environmental toxins, and viral infection in pathogenesis. These concepts must be considered in relation to what is known about the disease in all its aspects, including epidemiological data, information on the classical and molecular pathology of the disease, and on associated involvement of other systems, e.g., the spinocerebellar pathways and frontal dementia. Only when all this information is assimilated can full understanding of the disease and, hopefully, a logical approach to treatment and prevention, be achieved.