Cell migration and degradation of the extracellular matrix (ECM) are crucial steps in tumor progression. Several matrix-degrading proteases, including matrix metalloproteases, are highly regulated by growth factors, cytokines and ECM proteins. Osteopontin (OPN), a chemokine-like, calcified ECM-associated protein, plays a crucial role in determining the metastatic potential of various cancers. Since its first identification in bone, the multifaceted roles of OPN have been an area of intense investigation. Extensive research has elucidated the pivotal role of OPN in regulating the cell signaling that controls tumor progression and metastasis. This review focuses on recent advances in understanding the functional role of the OPN-induced signaling pathway in the regulation of cell migration and tumor progression and the implications for identifying novel targets for cancer therapy.