Most diseases that cause blindness do so as a result of neovascularization. Angiogenesis is a complex process regulated in adult tissues by a large interacting network of molecules. In pathological conditions the checks and balances of the angiogenesis system go awry and endothelial cells of the microvasculature, proliferate, migrate, and form new but leaky vessels that invade the tissue. Hemorrhaging vessels cause edema and damage to surrounding tissues, particularly the retina. Microvascular lesions often cause severe retinal detachment and loss of vision. In this review, the value of an important endogenous anti angiogenic molecule, PEDF, is discussed in relationship to its ability to prevent retinal cell death and counter the abnormal vessel growth induced by VEGF in the eye. Its control of a neuroprotective and an antineovascular regulatory axis that determines cell fate, and its possible use in combination therapeutic strategies for ocular neovascular diseases are also reviewed.