Recent breakthroughs in our understanding of the molecular pathophysiology of retinal vascular disease have allowed us to specifically target pathological angiogenesis while minimizing damage to the neurosensory retina. This is perhaps best exemplified by the development of therapies targeting the potent angiogenic growth factor and vascular permeability mediator, vascular endothelial growth factor (VEGF). Anti-VEGF therapies, initially introduced for the treatment of choroidal neovascularization in patients with age-related macular degeneration, have also had a dramatic impact on the management of retinal vascular disease and are currently an indispensable component for the treatment of macular edema in patients with diabetic eye disease and retinal vein occlusions. Emerging evidence supports expanding the use of therapies targeting VEGF for the treatment of retinal neovascularization in patients with diabetic retinopathy and retinopathy of prematurity. However, VEGF is among a growing list of angiogenic and vascular hyperpermeability factors that promote retinal vascular disease. Many of these mediators are expressed in response to stabilization of a single family of transcription factors, the hypoxia-inducible factors (HIFs), that regulate the expression of these angiogenic stimulators. Here we review the basic principles driving pathological angiogenesis and discuss the current state of retinal anti-angiogenic pharmacotherapy as well as future directions.