Systemic lupus erythematosus (SLE) is a multisystemic disease, caused by a variety of factors, which lead to immunological abnormalities. Osteopontin (OPN) is a pleiotropic protein, important in bone remodeling and immune system signaling. OPN, produced by various cells, including immune cells, plays a key role in regulating T-helper 1/T-helper 2 balance, stimulating B lymphocytes to produce antibodies, regulating macrophages, neutrophils and inducing dendritic cells. OPN expression is influenced by genetic polymorphisms of its promoter, hormones and cytokines. Over expression of OPN has been associated with the pathogenesis of immune-mediated diseases. OPN has been implicated in the development of murine model of lupus and in humans with SLE. In this review, I will present current state of research on the role of OPN and OPN gene polymorphisms in pathogenesis and clinical course of SLE. A better understanding of the role of OPN in SLE will contribute to more precise diagnosis and treatment of the disease.