The catabolic, degradative capacity of the endo‐lysosome system is put to good use in mammalian immune responses as is their recently established status as signaling platforms. From the ‘creative destruction’ of antigenic and ‘self’ material for antigen presentation to T cells to the re‐purposing of lysosomes as toxic exocytosable lysosome‐related organelles (granules) in leukocytes such as CD8 T cells and eosinophils, endo‐lysosomes are key players in host defense. Signaled responses to some pathogen products initiate in endo‐lysosomes and these organelles are emerging as important in distinct ways in the unique immunobiology of dendritic cells. Potential self‐inflicted toxicity from lysosomal and granule proteases is countered by expression of serpin and cystatin family members.