Osteopontin (OPN) is a protein involved in various pathophysiological events. OPN has been studied as a secreted protein, but recent reports showed that OPN can be found in the cytoplasm and the nucleus. Therefore, some OPN molecules are not secreted and stay in cells. Such intracellular OPN (iOPN) has biological functions distinct from secreted OPN (sOPN). iOPN is involved in cytoskeletal rearrangement and in signal transduction pathways downstream of innate immune receptors, such as Toll-like receptors (TLRs), as an adaptor or scaffolding protein. Although sOPN and iOPN are generated from the same Opn mRNA species, biological outcomes mediated by two isoforms can be different. It would be necessary to delineate which isoform of OPN is responsible for pathophysiological events.