Diseases complicated by abnormal growth of vessels or excessive leakage are the most prevalent cause of moderate or severe vision loss in developed countries. Recent progress unraveling the molecular pathogenesis of several of these disease processes has led to new drug therapies that have provided major benefits to patients. However, those treatments often require frequent intraocular injections, and despite monthly injections, some patients have a suboptimal response. Gene transfer of antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization (NV) and/or excessive vascular leakage in the eye. Studies in animal models of ocular NV have demonstrated impressive results with a number of transgenes, and a clinical trial in patients with advanced neovascular age-related macular degeneration has provided proof-of-concept. Two ongoing clinical trials, one using an adeno-associated viral (AAV) vector to express a vascular endothelial growth factor-binding protein and another using a lentiviral vector to express endostatin and angiostatin, will provide valuable information that should help to inform future trials and provide a foundation on which to build.