(A) In the normal retina, rod and cone photoreceptor outer segments are composed of thousands of photopigment-containing membrane discs that are continuously shed from the tips of the cells and recycled. The discarded discs are removed by RPE phagocytosis and reprocessed. (B) Additionally, microglia expressing CX3CR1 phagocytize cellular debris caused by daily insults (such as aging and cellular stress) and help maintain a healthy eye. (C) AMD resulting from loss of CX3CR1 expression is initiated by the same daily insults. However, as reported by Combadière et al. (6), when microglia lacking CX3CR1 are recruited to the area of damage they remain there, in part because of abnormal migration. CX3CR1-deficient microglia are proinflammatory (versus antiinflammatory CX3CR1-replete microglia; ref. 16) and recruit other proinflammatory cells. This response exacerbates the cellular damage that occurs with normal degeneration. (D) The increased accumulation of proinflammatory, CX3CR1-negative (16) microglia in the subretinal space appears to add to the formation of drusen (6), which contribute to loss of RPE function and photoreceptor degeneration (dry AMD). (E) Finally, as drusen build up and separate the RPE from the choroidal vasculature, the resulting hypoxia triggers proangiogenic signals, which foster choroidal neovascularization (wet AMD).