Multiple sclerosis (MS) is a demyelinating autoimmune disease. However, the persisting neurological deficits in MS patients result from acute axonal injury and chronic neurodegeneration, which are both triggered by the autoreactive immune response. Innate immunity, mainly mediated by activated microglial cells and invading macrophages, appears to contribute to chronic neurodegeneration. Activated microglia produce several reactive oxygen species and proinflammatory cytokines which affect neuronal function, integrity and survival. Adaptive immunity, particularly in cytotoxic CD8+ T cells, participates in acute demyelination and axonal injury by directly attacking oligodendrocytes and possibly neurons as well. Understanding the mechanisms of immune-mediated neuronal damage might help to design novel therapy strategies for MS.