Classical knowledge distinguishes between inflammatory and non-inflammatory diseases of the brain. Either the immune system acts on the CNS and initiates a damage cascade, as in autoimmune (e.g. multiple sclerosis) and infectious conditions, or the primary insult is not inflammation but ischemia or degeneration, as in stroke and Alzheimer's disease, respectively. However, as we review here, recent advances have blurred this distinction. On the one hand, the classical inflammatory diseases of the brain also exhibit profound and early neurodegenerative features - remarkably, it has been known for more than a century that neuronal damage is a key feature of multiple sclerosis pathology, yet this was neglected until very recently. On the other hand, immune mechanisms might set the pace of progressive CNS damage in primary neurodegeneration. Despite differing initial events, increasing evidence indicates that even in clinically heterogeneous diseases, there might be common immunological pathways that result in neurotoxicity and reveal targets for more efficient therapies.