Age-related macular degeneration (AMD) affects about one fifth of the population older than 65 years and is one of the main causes of poor vision in the elderly in industrialized nations. The endogenous lipophilic and cationic compound N-retinyl-N-retinylidene ethanolamine (A2E) is suspected to cause the dry form of the disease, which currently cannot be treated. The authors recently reported that A2E induces apoptosis in several cell types including porcine retinal pigment epithelial cells, detaches pro-apoptotic proteins from mitochondria, and inhibits cytochrome c oxidase. A2E acts primarily at the level of cardiolipin/cytochrome c oxidase, which in the light becomes permanently inactivated by A2E. The authors now report that A2E at low concentrations causes apoptosis in cultured human retinal pigment epithelial cells. These cells are more sensitive to A2E in the light than in the dark. Phosphatidylglycerol, a negatively charged phospholipid and immediate biosynthetic precursor of cardiolipin readily inhibits apoptosis. Exposure of cells to A2E results in the formation of reactive oxygen and nitrogen species, and exposure of mitochondria to A2E results in oxidative stress. Accordingly, the potent antioxidant coenzyme Q also protects cells against A2E-induced apoptosis. These findings are highly relevant for the treatment and/or prevention of AMD.