Oxidative stress is an important factor in the etiology of age-related macular degeneration. In the retinal pigment epithelium, oxidative stress induces protective pathways, notably the phosphatidylinositide 3-kinase (PI3K)/Akt and the nuclear factor erythroid-2 related factor 2 (Nrf2) pathways, but also vascular endothelial growth factor (VEGF) and neuroprotectin D1 (NPD-1) signaling conduct cell protection. Strong oxidative insults result in cell death, mainly mediated via a mitochondrial apoptotic pathway, including cytochrome c release and caspase activation. The role of mitogen activated protein kinases (MAPK) in oxidative stress signaling is diverse and conflicting, conducting protective as well as apoptotic pathways, in addition to involvement in a variety of other cell responses, such as VEGF or matrix metalloproteinases (MMP) upregulation. In addition to signaling deciding cell fate, first insights in inflammatory and extracellular matrix-altering signaling are emerging.