TNF-β (tumour necrosis factor-β) is a pleiotropic cytokine with wide-ranging actions on the immune system and is an important mediator in immune-mediated inflammatory disease states, including multiple sclerosis. TNF-β and its receptors are part of a large and complex superfamily of homologous ligands and receptors, whose many biological functions overlap. Investigations have demonstrated the effects of TNF-β at various stages of pathology in multiple sclerosis (MS), including oligodendrocyte death, demyelination, immune cell trafficking, cellular proliferation and major histocompatibility (MHC) antigen expression. Targeting the TNF-β immunobiological pathway successfully ameliorates disease severity in a number of autoimmune inflammatory conditions except for multiple sclerosis. Anti-TNF-β therapy in experimental autoimmune encephalomyelitis (EAE) showed mixed results, whereas in MS trials it was deleterious. It is clear that TNF-β also has a beneficial role, especially in neuroprotection and regeneration. A clearer understanding of the protective role of TNF-β may be extrapolated from studies in other inflammatory conditions such as stroke and traumatic brain injury.