<p>Lysosomes, central to protein and organelle homeostasis in all cells, have more recently been recognized as critical to other cellular processes, including nutrient sensing, cell metabolism, immune response, and programmed cell death. Tied into these varied functions, their composition as well as location within cells, lysosomes are now recognized to be made of heterogeneous subpopulations. Mechanisms that build and help maintain lysosome heterogeneity, its role in cell physiology, and links to pathologies are only now being worked out. Lysosome dysfunction has been associated with the pathogenesis of several neurodegenerative diseases. Neurons, which are particularly sensitive to lysosome dysfunction, are perhaps where lysosome biogenesis and transport, as well as its heterogeneity, are best studied in the nervous system. However, there is a growing interest in understanding lysosomal biogenesis and trafficking in other cell types of the nervous system, including microglia. In this review, we focus on key studies that have shed insight into microglial lysosome biology: its regulation, composition, and function, and how these properties are linked to immune activation, aging, and certain disease pathologies.</p>