Thrombospondin-1 (TSP-1) was one of the first endogenous inhibitors of angiogenesis to be discovered. This large multimodular protein of around 600 kDa inhibits endothelial cell proliferation, migration and morphogenic organization into capillary tubes. TSP-2 shares homology with TSP-1 in primary sequence, structural organization and angiostatic properties. TSP-1-null and TSP-2-null mice display increased tissue vascularity and enhanced sensitivity to carcinogenesis. Conversely, overexpression of TSP-1 or TSP-2 in cancer cells results in reduced tumor vascularization and tumor growth. In this review, we focus on the preclinical data obtained in experimental anti-tumorigenic assays using either TSP-1, TSP-2 or shorter peptides derived from the type 1 repeats of these molecules. In contrast with the full length thrombospondin molecules, which present a poor bioavailability and are highly susceptible to proteolytic degradation, TSP-derived angiostatic peptides appear as potent and promising therapeutic agents in anti-angiogenic therapy.