Angiogenesis, the process by which capillaries sprout from preexisting blood vessels, is tightly regulated by a large number of proangiogenic and antiangiogenic factors. To control pathological neovascularization, it is critical to understand the signaling cascades induced by inducers and inhibitors of angiogenesis in vascular endothelial cells, their outcome, and possible interplay among pathways. PEDF blocks angiogenesis by inducing programmed cell death in the activated endothelial cells. This mechanism is complex and consists of more than one cascade, all of which contribute to the final outcome. We unraveled one of the pathways where PEDF interferes with proangiogenic vascular endothelial growth factor. PEDF induced activation of the c-Jun N-terminal kinase JNK-1 and thus prevented dephosphorilation and consecutive activation/nuclear translocation of NFAT transcription factor. This can affect the transcriptional activation of genes whose overexpression is correlated to tumor growth, such as cyclooxygenase-2, or of those that interfere with cell death, as does FLICE-inhibitory protein (FLIP).