Osteopontin (OPN) is an extracelluar matrix protein with chemokine, cytokine and intergrin properties. It has multiple immunological functions and is secreted by activated macrophages, leukocytes and activated T lymphocytes. It is present in extracellular fluids and is up-regulated at sites of inflammation. OPN has intracellular and secreted isoforms. It has been shown to be involved in inflammation and autoimmune disorders, including multiple sclerosis. Multiple sclerosis (MS) is an immune mediated inflammatory disease of the central nervous system (CNS) in which autoreactive T cells attack the myelin-oligodendrocyte complex. Experimental autoimmune encephalomyelitis (EAE) is a widely used experimental model for MS. This review presents updated evidence for the role of OPN in MS and EAE, starting with the data provided by microarray analysis showing elevated levels of OPN transcripts in MS brain lesions and spinal cords of rats with EAE. This plausible target has since been validated in EAE, by showing that OPN knockout mice are protected from severe EAE. Increased levels of OPN were reported in plasma and CSF of MS patients in comparison to healthy controls. Potential mechanisms of OPN involvement in inflammatory demyelination are discussed. The involvement of OPN, in part via non-immune effects, in remyelination and its neuroprotective potential need to balanced against its pro-inflammatory properties.