The life history of melanin and lipofuscin granules of human retinal pigment epithelium (RPE) was studied in 30 human eyes spanning nine decades of life. Autofluorescent granules in the cytoplasm of eye over 30 years of age were shown, ultrastructurally and through lipid solvent extraction, to be lipofuscin granules. Sparse small fluorescent granules in infant eyes were secondary lysosomes containing small droplets of lipid. Flourescent substances in RPE granules of eyes less than 50 years old were more readily extracted with lipid solvents than those in very old eyes (greater than 70). Lipfuscin granules were positive for acid phosphatase and aryl sulfatase activity. Fusions between primary lysosomes and lipofuscin granules were common in older eyes, suggesting that the over-all degradative process involves repeated injection of lysosomal enzymes, i.e., the initial fusion of lysosomes with phagosomes (phagocytized outer segment disks) is only one of several attempts to hydrolyze the membranous material. Some melanin granules showed hydrolytic enzyme reactions. By use of enzyme cytochemistry, fluorescence microscopy, and lipid extraction two types of melanin-containing complex granules were identified: melanin with a cortex of lipofuscin (melanolipofuscin) and melanin with a cortex of nonlipid, enzyme reactive material (melanolysosomes). These findings indicate that melanin commonly becomes incorporated into the lysosomal system of the RPE cell and suggests that it undergoes modification or degradation there. These studies indicate that a dynamic, complex interrelationship exists between the various components of the phagolysosomal system and the melanin granules in the RPE cytoplasm. Also, the observed variation from one human eye to another in the content and lipid extractability of RPE lipofuscin granules suggests that there may be differences in lipid composition of phagocytized photoreceptor disks and/or differences in the degradation of these lipids in the phagolysosomal system of the RPE cell.