A matricellular protein, osteopontin (OPN), is expressed in response to mechanical stress and similar stimuli in the heart, integrates the inter-ECM signal transduction network of component cells, and maintains efficient contractility through quantitative and qualitative control of extracellular matrix (ECM) proteins. In particular, OPN is re-expressed in the process of tissue damage; combines with other cell growth factors, cytokines, chemokines, and proteases as a cytokine itself or as an adhesion molecule; and controls the differentiation and growth of cells involved in restoration of tissues by controlling inter-cellular signal transduction and production of ECM proteins through regulation of expression levels and activity. A study using mice lacking a functional OPN gene indicated that tissue restoration fails and collagen deposition is inhibited through matrix metalloproteinases (MMPs) in mice lacking OPN. Thus, while OPN accelerates the cardiovascular remodeling process, it also regulates the balance of various inter-cellular activities. In addition, OPN not only promotes arteriosclerosis but is also closely associated with angiogenesis. With the roles of OPN expected to be clinically elucidated, the clinical use of OPN for control of cardiovascular remodeling may be feasible. Points (1) Osteopontin (OPN) efficiently propagates contraction in the heart as a matricellular protein and thereby controls ECM proteins both quantitatively and qualitatively. (2) The quantitative and qualitative control of ECM proteins is involved in interaction with OPN receptors including those of the integrin family, CD44, and others. (3) OPN promotes myocardial remodeling through TGFbeta and MMPs. (4) OPN not only promotes arteriosclerosis but is also closely associated with arteriosteogenesis. (5) In animals lacking OPN, tissue remodeling process is inhibited, especially in terms of fibrosis after myocardial infarction. (6) While the significance of OPN as an immune system molecule is still unclear in detail, the significance of OPN in the regenerative immune system has begun to be determined.