Pigment epithelium derived factor (PEDF) is a potent and broadly acting neurotrophic factor that promotes survival of neurons in many regions of the CNS from degeneration caused by serum withdrawal or glutamate cytotoxicity and oxidative damage. PEDF is synthesized and secreted by retinal pigment epithelial (RPE) cells in early embryogenesis and is present in the ECM between the RPE cells and the neural retina. Protection against glutamate excitotoxicity in cerebellar granule neurons by PEDF involves activation of the NF-κB signaling cascade and the subsequent expression of anti-apoptotic and neuroprotective genes. PEDF induces expression of apoptosis related genes BCL2 , BCLX, or SOD in immature cerebellar granule cells but causes a long-lasting induction of NGF, BDNF and GDNF. The control of apoptotic signals by PEDF may also be linked to its regulation of Flip1, an inhibitor of caspase 8 and a key mediator of cell death. Flip1 is expressed above physiological levels when VEGF activates NF-κB in endothelial cells. PEDF restores physiological levels of Flip1 in the presence of VEGF in endothelial cells and thus may restore activity of the caspase 8 executioner pathway. PEDF also activates the Ras/Raf/MEK/ERK signaling pathway. Activated ERK regulates transcription factors such as TCF, Elk-1 and SRF thereby regulating gene expression. PEDF is known to drive the amoeboid-to-mesenchymal transition. It mediates this function by inhibiting the RhoA/ROCK pathway which tends to drive cells toward amoeboid morphology while activating WAVE2 and the accumulation of mesenchymal cells.The signaling cascades that PEDF activates indicate its involvement in events that can lead to both survival and cell death. PEDF inhibits neovascularization in the corneal pocket assay and decreases migration of endothelial cells. PEDF protein levels in the eye are responsive to ambient oxygen tension with protein levels increasing with increasing oxygen. In fetal and adult human eye tissue, PEDF is expressed by the cornea, ciliary body and cells of the inner and outer retina. PEDF secreted by these cells accumulates in avascular spaces of the eye such as the aqueous humor, vitreous humor and the interphotoreceptor matrix where it acts as a major inhibitor of angiogenesis. The activity of PEDF equals or supersedes that of other anti-angiogenic factors, including angiostatin, endostatin and thrombospondin-1.