Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature.