SPARC is a matricellular glycoprotein that mediates interactions between cells and their microenvironment. It is produced at sites of tissue remodeling, where it regulates matrix deposition and turnover, cell adhesion, and signaling by extracellular factors, exerting profound effects on tissue architecture and cell physiology. During extensive matrix remodeling in neoplastic progression, SPARC is expressed in cancer-associated stroma and in malignant cells of some types, affecting tumor development, invasion, metastases, angiogenesis and inflammation. SPARC-induced changes in the tumor microenvironment can suppress or promote progression of different cancers depending on the tissue and cell type. Understanding the mechanism of matrix remodeling and its regulation by SPARC is essential for the development of new treatment strategies for highly aggressive cancers.