Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which the myelin sheath has been considered to be the primary target for many years. However, an increasing number of reports have focused on neurodegenerative aspects of the disease pathogenesis. Recent studies in post-mortem MS biopsies and in the animal model Experimental Autoimmune Encephalomyelitis (EAE) have shown that key features of neurodegeneration, i.e. axonal transection, neuronal cell atrophy and neuronal death already occur in early disease phases. Furthermore, it has become clear that irreversible disability correlates stronger with the neuronal affectation than with demyelination. However the cause of neuronal damage still remains elusive, since both demyelination-dependent and direct immune cell-mediated mechanisms have been suggested so far. Here, we summarize the current concepts and recently identified molecular mechanisms of inflammatory neurodegeneration in autoimmune CNS inflammation and highlight the role of different immune cells in the complex network of interactions leading to neuronal damage.