Within classical extracellular matrix (ECM) proteins, there are a unique group of proteins that should be regarded as a distinct functional group of molecules. Matricellular proteins including osteopontin (OPN) and tenascin-c (TN-C) are highly expressed at the pathological foci of various inflammatory diseases. Unlike classical ECM proteins, these are soluble proteins and induce cell motility and persistent inflammation rather than providing a scaffold for stable cell adhesion. Osteopontin is a pleiotropic cytokine expressed by various cells. Two forms of OPN are present. A secreted form of OPN (sOPN) is involved in generation of T helper type 1 (Th1) and Th17 cells that are pathogenic T cells for various autoimmune diseases. An intracellular form of OPN (iOPN) is a critical regulator for Toll like receptor-9 (TLR-9) and/or TLR-7-dependent interferon-α (IFN-α) expression by plasmacytoid dendritic cells (DCs) and Th17 development. Indeed, both OPN and TN-C deficient mice are resistant to various Th1- and/or Th17-related autoimmune diseases. Interestingly, thrombin-cleaved forms of sOPN and TN-C share a common integrin receptor, α9β1, and α9β1 integrin-mediated signaling is involved in the pathogenesis of various autoimmune diseases. Thus, OPN, TN-C and its common receptor, α9β1 integrin may serve as potential therapeutic targets for various intractable inflammatory diseases.