In this review most of the various known, suspected, or postulated functions of osteopontin, a secreted highly acidic phosphoprotein, are discussed in terms of what we currently know about the protein. These include 1) binding of OPN both to cells via a GRGDS cell adhesion sequence that recognizes the alpha(v)beta3 integrin and to extracellular matrix components via poorly characterized motifs, 2) regulation of the formation and remodeling of mineralized tissue, 3) recruiting and stimulating macrophages and lymphocytes as part of a nonspecific response to microbial infections, 4) multiple interactions with Ca2+ that likely influence OPN protein conformation and may be important in Ca2+-mediated of Ca2+-dependent processes, 5) inhibiting the growth of calcium oxalate crystals by disruption of the growing crystal lattice, 6) effects on gene expression, Ca2+ regulation, and nitric oxide production, and 7) involvement in cell migration. OPN production is frequently augmented when cell signaling pathways are activated by any of a variety of stimuli, for example in cancer cells.