Abstract: Lysosomes are highly dynamic, single membrane-bound compartments that are critical for maintaining cellular homeostasis. These organelles, which appear to vary between 200 nm–1 μm in diameter, originate from the maturation of endocytic vesicles and via the enrichment of newly synthesized lysosomal proteins in the trans-Golgi network. Lysosomes mediate the targeted degradation of intracellular and extracellular cargoes, including those trafficked by the endosomal and autophagic pathways, to produce monosaccharides, amino acids, and free fatty acids, among other molecules. However, recent discoveries have revealed additional lysosomal functions, including roles in nutrient and metabolic sensing, gene regulation, inflammation, membrane repair, and effects on the extracellular environment. Lysosomes are found throughout the cytoplasm, but may have a preferential distribution depending on their specific activity or cell state. For example, due to their origin, lysosomes predominantly localize to the perinuclear region, but also maintain this distribution under conditions of proteolytic stress. However, secretory lysosomes localize to the cell periphery and also appear to be less acidic (Keeling et al., 2018). Lysosomal positioning is also influenced by contact with the endoplasmic reticulum, mitochondria and the Golgi apparatus. Lysosomes are rarely stationary and are trafficked bidirectionally along microtubules, with anterograde and retrograde movements mediated by kinesin or dynein. While lysosomes are known to play a causative role in storage diseases, their broader dysfunction contributes to a variety of neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, age-related macular degeneration (AMD), amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease, among others (Keeling et al., 2018; Malik et al., 2019). Retinal pigment epithelial (RPE) cells provide a unique model to study lysosomal biology and the consequences of their dysfunction. The RPE forms a highly specialized monolayer in the retina that is intimately associated with photoreceptors. Overlying photoreceptors shed outer segments (photoreceptor outer segments, POS) as part of the daily photoreceptor renewal, which are engulfed and trafficked for degradation in lysosomes of RPE cells. Here, we review our novel findings showing how disease-related pathways in the retina affect these organelles and how lysosomal defects may contribute to RPE damage as part of a clinically well-defined pathway of RPE atrophy leading to irreversible vision loss in AMD and other retinopathies.