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 beta 3 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 Ca(2+)-mediated or Ca(2+)-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.