The skeleton is the most common site of tumor metastasis. The detection of metastatic bone disease is critical for primary cancer staging because it will condition the therapeutic decision and the prognosis. For the diagnosis of bone metastases, imaging techniques are usually employed, even if these techniques have some limitations in terms of accuracy and costs. An innovative, cheaper method for the screening of skeletal metastases could be the measurement of bone turnover markers. This article is aimed at providing a literature review on the clinical significance of increased serum levels of bone sialoprotein (BSP) observed in patients suffering from metastatic bone lesions. In addition, we have briefly summarized recent studies reporting the biological and pathological roles of BSP in bone remodeling and bone metastasis. Some studies have demonstrated that serum BSP can be considered as an early marker and a prognostic factor for the development of bone metastases. BSP may help in assessing osteolytic bone disease, in evaluating additional prognostic information and in monitoring treatment modalities.