Osteopontin (OPN) is a highly phosphorylated sialoprotein that is a prominent component of the mineralized extracellular matrices of bones and teeth. OPN is characterized by the presence of a polyaspartic acid sequence and sites of Ser/Thr phosphorylation that mediate hydroxyapatite binding, and a highly conserved RGD motif that mediates cell attachment/signaling. Expression of OPN in a variety of tissues indicates a multiplicity of functions that involve one or more of these conserved motifs. While the lack of a clear phenotype in OPN "knockout" mice has not established a definitive role for OPN in any tissue, recent studies have provided some novel and intriguing insights into the versatility of this enigmatic protein in diverse biological events, including developmental processes, wound healing, immunological responses, tumorigenesis, bone resorption, and calcification. The ability of OPN to stimulate cell activity through multiple receptors linked to several interactive signaling pathways can account for much of the functional diversity. In this review, we discuss the structural features of OPN that relate to its function in the formation, remodeling, and maintenance of bones and teeth.