Osteopontin (OPN) was initially identified in osteoblasts as a mineralization-modulatory matrix protein. Recently, OPN has been studied as a multifunctional protein that is upregulated in a variety of acute and chronic inflammatory conditions, such as wound healing, fibrosis, autoimmune disease, and atherosclerosis. OPN is highly expressed at sites with atherosclerotic plaques, especially those associated with macrophages and foam cells. In the context of atherosclerosis, OPN is generally regarded as a proinflammatory and proatherogenic molecule. However, the role of OPN in vascular calcification (VC), which is closely related to chronic and active inflammation, is that of a negative regulator because it is an inhibitor of calcification and an active inducer of decalcification. OPN expression and its regulatory molecular mechanisms remain elusive during the process of VC. Therefore, further research with regard to the role of OPN in diseases associated with VC is needed to identify potential OPN-related therapeutic targets.