It has been well recognized that inflammatory responses are part of pathogenesis for various disorders such as autoimmune diseases. For example, multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system that is presumably caused by activated T cells specific for myelin antigens. Rheumatoid arthritis (RA) is also a chronic inflammatory disease characterized by synovial inflammation in which several inflammatory cytokines are involved. On the other hand, Osteopontin (Opn) is a pleiotropic cytokine expressed by activated T cells, dendritic cells (DCs) and macrophages and its expression is up-regulated during inflammation. Secreted form of Opn (s-Opn), which is modified by phosphorylation, glycosylation and proteolytic cleavage with thrombin, has activities as a T helper type 1 (Th1) cytokine and as a chemoattractant for many types of cells through integrin receptors and CD44. Recently, it has been uncovered that intracellular form of Opn (i-Opn) is a critical regulator for Toll like receptor-9 (TLR-9), TLR-7-dependent interferon-alpha (IFN-alpha) expression by plasmacytoid DCs and Th17 development. In this review, we have summarized recent progress in understanding of Opn's role in variety of inflammatory disorders.