Multiple sclerosis is generally regarded as a putative autoimmune disease of the central nervous system in which a chronic T-cell-mediated inflammation leads to focal plaques of demyelination in the white matter of the central nervous system. This plaque-centered view of the disease, however, fails to explain clinical deterioration of the patients when they have reached the progressive stage of the disease. It was thus postulated during the past few years that besides inflammation there is a neurodegenerative component of the disease that leads to progressive and global brain damage. This article reviews recent findings that suggest a different explanation. It describes that in the early stage of acute and relapsing multiple sclerosis, focal plaques in the white matter are formed by relapsing waves of inflammation. With chronicity, however, the inflammatory response becomes trapped behind the blood-brain barrier, giving rise to slowly progressive inflammatory damage that affects the brain and spinal cord in a global sense. This is mainly reflected by extensive cortical demyelination and diffuse axonal injury within the normal-appearing white matter. This process seems to be driven by the aberrant formation of ectopic lymphatic tissue within the brain compartment.