During the carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are constitutively expressed. However, a synthetic inhibitor (SU5416) of VEGF signaling impairs angiogenic switching and tumor growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic by releasing VEGF. MMP inhibitors reduce angiogenic switching, tumor number, and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair angiogenic switching but retards tumor growth, whereas lack of urokinase has no effect. These results show that MMP-9 is a component of the angiogenic switch.During the carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are constitutively expressed. However, a synthetic inhibitor (SU5416) of VEGF signaling impairs angiogenic switching and tumor growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic by releasing VEGF. MMP inhibitors reduce angiogenic switching, tumor number, and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair angiogenic switching but retards tumor growth, whereas lack of urokinase has no effect. These results show that MMP-9 is a component of the angiogenic switch.