Growth factors in the eye exist in a critical balance in order to maintain retinal homeostasis. Aberrant regulation of both pro- and anti-angiogenic molecules results in the formation of abnormal vessels, or neovascularization. Neovascularization of the choroid or retina plays a significant role in blindness and contributes to the pathogenesis of diabetic retinopathy, age-related macular degeneration and retinal detachment. We hypothesized that the expression of key growth factors in neovascular models of retinal injury can be modulated to influence the disease process. Through the use of primary cultured rat retinal pigment epithelial cells and rat models of laser-induced neovascular retinal injury, choroidal neovascularization and surgically-induced retinal detachment, we investigated the role of vascular endothelial growth factor regulation in high glucose and hypoxia and the role of pigment epithelial derived factor in influencing models of neovascular retinal disease. We showed that the protein kinase C isozymes are important in vascular endothelial growth factor-mediated signaling in the retinal pigment epithelial cell type, and that protein kinase C-delta and protein kinase C-zeta exhibit differential responses to vascular endothelial growth factor, high glucose and hypoxic stimulation. Furthermore, we demonstrated that pigment epithelial derived factor may influence photodynamic therapy enhanced angiographic choroidal neovascular lesion closure. Finally we examined growth factors involved in experimentally-induced retinal detachment and the specific effect of pigment epithelial derived factor on this model of retinal injury. We found that pigment epithelial derived factor had little influence on this model. We conclude that the mechanisms of vascular endothelial growth factor production and regulation in the retinal pigment epithelial cell type are mediated by protein kinase C. Further study of this cell type in the regulation of angiogenesis in the eye is warranted. Additionally, the modification of growth factors in the ocular milieu of our in vivo models of retinal injury may have an influential role in the modification of the disease process which underscores the importance of developing new therapeutic strategies for ocular neovascular eye disease.