Lysosomes perform a range of functions, some of which, such as degradation, are common to all cell types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve fusion of this organelle with the cell surface to release its contents. This review describes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also review the characteristic changes in lysosomal hydrolases and membrane proteins in common autoimmune diseases. Finally, future directions in lysosome research are proposed, with it being suggested that the role of lysosomes will continue to be of growing interest in immunity research.