There is little doubt that multiple sclerosis (MS) is an immune mediated disease, yet the exact immunological mechanisms, that are responsible for inflammation and demyelination in this disease are controversial. Recent evidence is summarized here, which suggests that heterogeneous pathogenetic mechanisms may lead to the inflammatory demyelinating plaques in different MS patients. This heterogeneity apparently involves the antigen specificity of the immune response as well as the mechanisms, responsible for the destruction of myelin sheaths. Since such a pathogenetic heterogeneity may have consequences for the design of therapeutic studies, strategies are discussed, which should allow a more accurate categorization of patient sub-groups in the future.