Thrombospondins are a family of extracellular matrix (ECM) proteins. Thrombospondin-1 (TSP1) was the first member to be identified and is a main player in tumor microenvironment. The diverse functions of TSP1 depend on the interactions between its structural domains and multiple cell surface molecules. TSP1 acts as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, inhibiting endothelial cell migration and proliferation, and regulating vascular endothelial growth factor bioavailability and activity. In addition to angiogenesis modulation, TSP1 also affects tumor cell adhesion, invasion, migration, proliferation, apoptosis and tumor immunity. This review discusses the multifaceted and sometimes opposite effects of TSP1 on tumor progression depending on the molecular and cellular composition of the microenvironment. Clinical implications of TSP1-related compounds are also discussed.