Age-related macular degeneration (AMD), the largest cause of legal blindness in the elderly in the Western world, is a disease whose pathogenesis is incompletely understood and for which therapeutic challenges remain. The etiology of AMD is thought to involve chronic neuroinflammation of the retina but the details of relevant cellular mechanisms are still not fully understood. Retinal microglia are the primary resident immune cell in the retina and are normally absent from the outer retina, the locus of AMD. Their migration and infiltration into the outer retina under conditions of advanced age and disease implicate their involvement in the neuroinflammatory etiology of AMD. We propose that interactions between microglia and RPE cells in the subretinal space result in significant alterations in the structure and physiology of RPE cells that in turn transforms the environment of the retino-choroidal interface into one conducive for the progression and advancement of AMD. In particular, microglia induce RPE alterations that result in a more chemoattractive, pro-inflammatory, and pro-angiogenic environment that increases the recruitment and activation of immune cells and fosters the growth of neovascular vessels into the retina. Microglia-to-RPE influences may represent a cell-cell interaction that may be targeted for therapeutic strategies to treat and/or prevent AMD.