Thrombospondin-1 (TSP-1) and -2 are extracellular, calcium-binding proteins that regulate cellular phenotype by orchestrating the assembly of multiprotein complexes on the cell surface. These complexes include CD36, transforming growth factor beta, proteoglycans, integrins and integrin associated proteins. Thrombospondin-1 on the cell surface inhibits (1) proliferation of endothelial cells and tumor cells in vitro, (2) endothelial cell migration and angiogenesis, and (3) the growth of experimental and naturally occurring tumors in vivo. To establish a role for TSP-1 in the progression of spontaneously occurring tumors that arise at orthotopic sites in vivo, we have crossed mice that are deficient in TSP-1 with mice that are deficient in p53. Mice that lack TSP-1 exhibit decreased survival and altered tumor specturm. Consistent with these observations, overexpression of TSP-1 inhibits tumor growth and angiogenesis. In addition, systemic injection of recombinant type 1 repeats of TSP-1, designated 3TSR, inhibits the growth of experimental tumors formed from breast, colon, pancreatic, skin and ovarian cancer cells. 3TSR is particularly active in an orthotopic model of advance stage ovarian cancer with treated mice showing tumor regression and greatly increased survival in an intervention trial. Survival is further enhanced when 3TSR is combined with chemotherapy. Current research focuses on the development of a therapeutic form of 3TSR that can be used in the clinic.