Background Prostate cells secrete many molecules capable of regulating angiogenesis; however, which of these actually function as essential regulators of neovascularization is not yet clear. Methods Functional angiogenic mediators secreted by normal and diseased prostate cells were identified using an in vitro angiogenesis assay. These factors were quantified by immunoblot or ELISA and localized in tissue by immunohistochemistry. Results Normal prostate epithelial cell secretions were anti‐angiogenic due to inhibitory thrombospondin‐1 (TSP‐1) whereas this inhibitor was decreased in the pro‐angiogenic secretions derived from benign prostatic hyperplasia (BPH) and cancer cells. This pro‐angiogenic activity depended primarily on fibroblast growth factor‐2 (FGF‐2) and/or vascular endothelial growth factor (VEGF) whose secretion was increased. Immunolocalization studies confirmed that the changes detected in vitro also occurred in vivo. Conclusions During disease progression in the prostate, production of TSP‐1, the major inhibitor, is down‐regulated while that of stimulatory FGF‐2 and/or VEGF rise, leading to the induction of the new vessels necessary to support tumor growth. Prostate 49:293–305, 2001. © 2001 Wiley‐Liss, Inc.