Most diseases causing increased autofluorescence do so because of a corresponding increase in fluorophores in the retinal pigment epithelium (RPE). This chapter covers diseases and conditions causing increased autofluorescence generated from the outer retina and subretinal space in addition to the autofluorescence normally originating from the RPE (Fig. 17.1). This autofluorescence arising from the retina and subretinal space generally does not come from lipofuscin as such, because lipofuscin is a mixture of material found in an intracellular organelle, the lysosome. These diseases are generally associated with physical separation of the outer segments from the RPE, thus hindering normal phagocytosis of the shed outer segments of the photoreceptors. The shed photoreceptor outer segments are theorized to accumulate on the outer retina and in the subretinal space [1, 2].