Choroidal neovascularization (CNV) is the most severe complication in age-related macular degeneration. VEGF-A has been identified as the major angiogenic factor in CNV. Intraocular injections of substances that trap free VEGF-A represent the first intervention leading to vision improvement. New data imply a refinement by considering the Janus-like differential signaling at the VEGF receptor-1 leading to either pro- or antiangiogenic effects of VEGF-A to exploit possible antiangiogenic effects. Furthermore, the isoform VEGF-C appears to function synergistically with VEGF-A at endothelial cells and the retinal pigment epithelium. Thus, while the new therapies for CNV provide proof of principle for interventions at the VEGF signaling system, our recent discoveries regarding the dynamics of VEGF signaling provide new opportunities for more efficient approaches. © 2007, Future Drugs Ltd. All rights reserved.