Troponin I (TnI) is a novel cartilage-derived angiogenesis inhibitor, first demonstrated by Moses et al. (1999, Proc. Natl. Acad. Sci. USA 2645-2650) to inhibit endothelial cell proliferation and angiogenesis, both in vivo and in vitro, and to inhibit metastasis of a wide variety of tumors in vivo. Despite convincing evidence of its efficacy, little is known about the mechanism of action of TnI as an anti-proliferative and anti-angiogenic agent. In the current article we demonstrate that TnI inhibits both bFGF-stimulated and basal levels of endothelial cell proliferation, and we hypothesize that this inhibition is occurring, at least in part, via an interaction of TnI with the cell-surface bFGF receptor on capillary endothelial cells. We further support this hypothesis by providing the first evidence that TnI can act on nonendothelial as well as endothelial cells and by demonstrating that this inhibitory action is specific for the bFGF receptor on the target cells. Preliminary data suggest that TnI may be competing with bFGF for interaction with the bFGF receptor on responsive cells.