Fumagillin is an anti-angiogenic natural product from Aspergillus fumigatus that served as the structural parent for the anti-tumor drug candidate TNP-470 (AGM1470). Our lab was the first to show that fumagillin/TNP-470 covalently binds and inhibits the metalloprotease methionine aminopeptidase 2 (MetAP-2). Our subsequent studies showed that the selective endothelial cytostatic activity of fumagillin/TNP-470 requires p21CIP/Waf for its G1 cell cycle arrest. In addition, our MetAP-2 knockout mouse validated this protein as a new anti-angiogenic drug target. More recently, we have shown that MetAP-2 inhibition perturbs the non-canonical Wnt/Planar Cell Polarity (PCP) pathway and that genetic disruption of PCP signaling blocks normal endothelial cell biology. These results suggest that other small molecule PCP inhibitors could serve new anti-angiogenic drug candidates.