The “golden years” are much less so if you lose your central vision to neovascular age-related macular degeneration (AMD). Approximately 15 out of 1000 individuals over age 75 will have advanced AMD; 66% will have the neovascular form that is associated with central vision loss. The introduction of anti-VEGF treatment for neovascular AMD 15 years ago (1) has revolutionized care for these patients, much as pan-retinal photocoagulation (PRP) did for patients with proliferative diabetic retinopathy (PDR) and ischemic retinal vein occlusions (RVOs) decades earlier. The difference between these two therapeutic advances is that PRP reduces the ischemic drive by destroying portions of the peripheral retina while VEGF antagonists do little to relieve underlying hypoxia. In addition to having potent vasopermeability and some angiogenic activity, VEGF is an important neurovasculotrophic factor that is critical to the survival and function of neurons and endothelial cells. Because neurovascular cell functions are already compromised by underlying disease (eg, AMD, diabetes, RVOs), potent, long-lasting VEGF antagonism may be detrimental to the health of cells dependent on its trophic activity. Patients with ischemic (eg, diabetes, ARMD) retinopathies are likely to have ischemia elsewhere (eg, heart, brain, kidneys), and the sustained presence of potent VEGF antagonists may prevent adequate collateralization and function in these tissues as well. While the less potent and long-lasting VEGF antagonist drugs may be “just bad enough,” newer therapies that are far more potent and/or longer lasting may precipitate problems from suppressed VEGF activity. We will discuss issues to consider when treating ocular disease with VEGF antagonists.