Multiple sclerosis (MS) is a commonly occurring inflammatory and demyelinating neurological disease. It has been considered to be an autoimmune disorder mediated by CD4⁺ type 1 T helper cells, but recent studies have challenged this idea by indicating a role for other immune cells. So, T- and B-cell responses in the brain of patients with MS involve the clonal expansion of lymphocytes and the antigen-driven maturation of the B-cell receptors, indicating that the immune response in MS engages a broad range of immune cells that target a limited number of brain antigens. At variance with the classical view, axons are not spared during the inflammatory process. Indeed, axonal damage determines clinical outcome to a large extent. Studies of the mechanisms of axonal damage and neurodegeneration in MS are in their infancy. Here, we summarize recent advances in our understanding of the pathogenesis of MS, and conclude with an outlook on how to capitalize on this knowledge to develop new therapeutic approaches.